Heterocyclic cetp inhibitors

ABSTRACT

Compounds of formula Ia and Ib 
     
       
         
         
             
             
         
       
     
     wherein A, B, C and R 1  are described herein.

RELATED APPLICATION

This application is a divisional of prior U.S. patent application Ser.No. 12/797,760, filed on Jun. 10, 2010, now allowed, which claimspriority benefit of U.S. patent application Ser. No. 11/558,979 filedNov. 13, 2006, issued as U.S. Pat. No. 7,790,770 B2, which claims thebenefit of U.S. Provisional Application No. 60/739,374, filed on Nov.23, 2005. The entirety of each of these applications is incorporatedherein by reference.

FIELD OF THE INVENTION

This present invention provides for cholesteryl ester transfer protein(CETP) inhibitors, pharmaceutical compositions containing suchinhibitors and the use of such inhibitors to elevate certain plasmalipid levels, including high density lipoprotein (HDL)-cholesterol andto lower certain other plasma lipid levels, such as low densitylipoprotein (LDL)-cholesterol and triglycerides and accordingly to treatdiseases which are affected by low levels of HDL cholesterol and/or highlevels of LDL-cholesterol and triglycerides, such as atherosclerosis andcardiovascular diseases in certain mammals (i.e., those which have CETPin their plasma), including humans.

BACKGROUND OF THE INVENTION

Atherosclerosis and its associated coronary artery disease (CAD) is theleading cause of mortality in the industrialized world. Despite attemptsto modify secondary risk factors (smoking, obesity, lack of exercise)and treatment of dyslipidemia with dietary modification and drugtherapy, coronary heart disease (CHD) remains the most common cause ofdeath in the U.S., where cardiovascular disease accounts for 44% of alldeaths, with 53% of these associated with atherosclerotic coronary heartdisease.

Risk for development of atherosclerosis has been shown to be stronglycorrelated with certain plasma lipid levels. While elevated LDL-C may bethe most recognized form of dyslipidemia, it is by no means the onlysignificant lipid associated contributor to CHD. Low HDL-C is also aknown risk factor for CHD (Gordon, D J. et al., “High-densityLipoprotein Cholesterol and Cardiovascular Disease”, Circulation,(1989), 79:8-15).

High LDL-cholesterol and triglyceride levels are positively correlated,while high levels of HDL-cholesterol are negatively correlated with therisk for developing cardiovascular diseases. Thus, dyslipidemia is not aunitary risk profile for CHD but may be comprised of one or more lipidaberrations.

Among the many factors controlling plasma levels of these diseasedependent principles, cholesteryl ester transfer protein (CETP) activityaffects all three. The role of this 70,000 dalton plasma glycoproteinfound in a number of animal species, including humans, is to transfercholesteryl ester and triglyceride between lipoprotein particles,including high density lipoproteins (HDL), low density lipoproteins(LDL), very low density lipoproteins (VLDL), and chylomicrons. The netresult of CETP activity is a lowering of HDL cholesterol and an increasein LDL cholesterol. This effect on lipoprotein profile is believed to bepro-atherogenic, especially in subjects whose lipid profile constitutesan increased risk for CHD.

No wholly satisfactory HDL-elevating therapies exist. Niacin cansignificantly increase HDL, but has serious toleration issues whichreduce compliance. Fibrates and the HMG CoA reductase inhibitors raiseHDL-C only modestly (about 10-12%). As a result, there is a significantunmet medical need for a well-tolerated agent which can significantlyelevate plasma HDL levels, thereby reversing or slowing the progressionof atherosclerosis.

Thus, although there are a variety of anti-atherosclerosis therapies,there is a continuing need and a continuing search in this field of artfor alternative therapies.

SUMMARY OF THE INVENTION

In accordance with the present invention, heterocyclic compounds andrelated compounds are provided that have the general structures:

wherein A, B, C and R₁ are defined below.

By use of a respective effective amount of at least one compounddescribed herein, provided are methods of treating, preventing orslowing the progression of a disease requiring cholesteryl estertransfer protein inhibition, or inhibiting the cholesteryl estertransfer protein.

Also provided are pharmaceutical compositions comprising atherapeutically effective amount of at least one compound describedherein and a pharmaceutically acceptable vehicle or carrier thereof.Such compositions can further comprise one or more additionaltherapeutic agents.

DEFINITIONS

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,pentyl, hexyl, heptyl, octyl, or any subset of the foregoing. The term“substituted alkyl” refers to alkyl groups substituted with one or moregroups (such as by groups described above in the definition of R¹⁰),such as selected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone double carbon to carbon bond (either cis or trans), such as ethenyl.The term “substituted alkenyl” refers to alkenyl groups substituted withone or more groups (such as by groups described above in the definitionof R¹⁰), such as selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane and sulfonyl, or any subset of the foregoing.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone triple carbon to carbon bond, such as ethynyl. The term “substitutedalkynyl” refers to alkynyl groups substituted with one or more groups(such as by groups described above in the definition of R¹⁰), such asselected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “aryl” refers to aromatic homocyclic (i.e., hydrocarbon) mono-,bi- or tricyclic ring-containing groups such as having 6 to 12 memberssuch as phenyl, naphthyl and biphenyl. Phenyl is an example of an arylgroup. The term “substituted aryl” refers to aryl groups substitutedwith one or more groups (such as by groups described above in thedefinition of R¹⁰), such as selected from alkyl, substituted alkyl,alkenyl (optionally substituted), aryl (optionally substituted),heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl, (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane and sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “cycloalkyl” refers to mono-, bi- or tri homocyclic ring groupsof 3 to 15 carbon atoms which are, respectively, fully saturated andpartially unsaturated. The rings of multi-ring cycloalkyl groups may beeither fused, bridged and/or joined through one or more spiro unions.The term “substituted cycloalkyl” refers to a cycloalkyl groupsubstituted with one or more groups (such as by groups described abovein the definition of R¹⁰), such as selected from aryl, substituted aryl,heterocyclo, substituted heterocyclo, carbocyclo, substitutedcarbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy(optionally substituted), alkylester (optionally substituted), arylester(optionally substituted), alkanoyl (optionally substituted), aryol(optionally substituted), cyano, nitro, amino, substituted amino, amido,lactam, urea, urethane and sulfonyl, or any subset of the foregoing.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclyl” refer to fully saturated or partially or completelyunsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclicgroups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring memberbicyclic, or 10 to 20 ring member tricyclic ring systems, such as, incertain embodiments, a monocyclic or bicyclic ring containing a total of3 to 10 ring atoms) which have at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be either fused, bridged and/orjoined through one or more spiro unions.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl,tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls(such as 6-azabicyclo[3.2.1]octane), azaspiroalkyls (such as 1,4dioxa-8-azaspiro[4.5]decane), imidazopyridinyl (such asimidazo[1,5-a]pyridin-3-yl), triazolopyridinyl (such as1,2,4-triazolo[4,3-a]pyridin-3-yl), and hexahydroimidazopyridinyl (suchas 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-3-yl),

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclyl” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups (such as by groups described above in the definition ofR¹⁰), such as selected from alkyl, substituted alkyl, alkenyl, oxo,aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo(optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amido,amino, substituted amino, lactam, urea, urethane, sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formulas Ia and Ib form salts or solvates which arealso within the scope of this invention. Reference to a compound of theformula Ia or Ib herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic and/or basic salts formed with inorganic and/ororganic acids and bases. In addition, when a compound of formula Ia orIb contains both a basic moiety and an acidic moiety, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also useful, e.g., in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula Iaand Ib may be formed, for example, by reacting a compound of formula Iaor Ib with an amount of acid or base, such as an equivalent amount, in amedium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

The compounds of formula Ia and Ib which contain a basic moiety may formsalts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula Ia and Ib which contain an acidic moiety mayform salts with a variety of organic and inorganic bases. Exemplarybasic salts include ammonium salts, alkali metal salts such as sodium,lithium, and potassium salts, alkaline earth metal salts such as calciumand magnesium salts, salts with organic bases (for example, organicamines) such as benzathines, dicyclohexylamines, hydrabamines (formedwith N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g. benzyl and phenethyl bromides), and others.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., a compound of formula Ia or Ib) is a prodrug within thescope and spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula Ia andIb with alkyl, alkoxy, or aryl substituted acylating agents employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31(Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds., Ch. 5, pp. 113-191 (Harwood Academic Publishers,1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer, (Wiley-VCH, 2003).

Said references are incorporated herein by reference.

In addition, compounds of the present invention are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Iaor Ib compound (“substantially pure” compound Ia or Ib), which may beused or formulated as described herein. Such “substantially pure”compounds of formula Ia and Ib are also contemplated herein as part ofthe present invention.

To the extent that compounds of the formula Ia and Ib, and saltsthereof, may exist in their tautomeric form, all such tautomeric formsare contemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons) and diastereomeric forms, are contemplated within the scope ofthis invention. Individual stereoisomers of the compounds of theinvention may, for example, be substantially free of other isomers, ormay be admixed, for example, as racemates or with all other, or otherselected, stereoisomers.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

It will be understood that any given exemplary embodiment can becombined with one or more additional exemplary embodiments.

In accordance with the present invention, compounds of formula Ia and Ibare provided

or stereoisomers or prodrugs or pharmaceutically acceptable salt formsthereof, wherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)—S(O)_(p)R₆, 18) SO₂NHR₆, 19) —COOR₆, 20) —NHC(CN)NHR₆, 21) —CONR₆R₆,22) (C₂-C₆)-alkynyl, which may be optionally substituted with one ormore R₂₀'s, 23) (C₂-C₆)-alkenyl, which may be optionally substitutedwith one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆, 26) —OCONR₆R₆, or 27)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or any two adjacent substituents may join together to form a 4- to8-membered ring, which optionally may contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R₂₀'s;

B is:

-   -   (a) phenyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆; and 21) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (b) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆; and 21) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;

C is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)        —SO₂NHR₆, 16) —COR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which        may be optionally substituted with one or more R₂₀'s;    -   (b) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl; and 15) cycloalkyl, which may be optionally        substituted with one or more R₂₀'s;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)        —SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (d) heterocyclo, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)₆R₆, 15)        —SO₂NHR₆, 16) —COR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which        may be optionally substituted with one or more R₂₀'s;

R₁ is H, —C(O)R₃, —C(O)NR₂R₃, —C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₅, or—C(S)R₃;

R₂ is:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17)        —SO₂NHR₆, 18) —COR₆, 19) —NHC(CN)NHR₆; and 20) cycloalkyl, which        may be optionally substituted with one or more R₂₀'s;    -   (c) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20) —SO₂NHR₆, 21)        —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s; or    -   (d) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂        (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, 20)        (C₂-C₆)-alkynyl; and 21) cycloalkyl, which may be optionally        substituted with one or more R₂₀'s;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COR₆, 19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)        —S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) NHC(CN)NHR₆; and 24)        cycloalkyl, which may be optionally substituted with one or more        R₂₀'s; or    -   (f) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20) —SO₂NHR₆, 21)        —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;        or R₂ and R₃ are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₄ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, 23) —NHC(CN)NHR₆; and 24) cycloalkyl, which may be        optionally substituted with one or more R₂₀'s;    -   (d) (C₂-C₆)-alkenyl; or    -   (e) (C₂-C₆)-alkynyl;

R₅ is arylalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆,        or 23) cycloalkyl, which may be optionally substituted with one        or more R₂₀'s;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)        —NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally        substituted with one or more R₂₀'s;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)        —NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally        substituted with one or more R₂₀'s;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;    -   (f) hydrogen;    -   (g) alkynyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (h) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;        or two R₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₇ is aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆,20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;

R₅ can independently be:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, 18) —S(O)_(p)R₂₆, 19)        —SO₂NHR₂₆, 20) —COOR₂₆, 21) —NHC(CN)NHR₂₆; and 22) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;    -   (c) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;    -   (d) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;    -   (e) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (f) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20)        —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;        and 24) cycloalkyl, which may be optionally substituted with one        or more R₂₀'s;        or two R₈'s are taken together to form a 3- to 9-membered ring,        which may optionally contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₉ and R₁₀ are independently: (a) hydrogen; (b) —[(C═O)O_(r)]_(s)aryl,wherein the aryl may be optionally substituted with one or more R₂₀'s;(c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may beoptionally substituted with one or more R₂₀'s; (d)[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; (e) heterocyclyl optionallysubstituted with one or more R₂₀'s; (f) —CONR₂₆R₂₆; (g)—(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j) —SO₂NHR₂₆; (k)—COOR₂₆; (l) —NHC(CN)NHR₂₆; or m) —[(C═O)O_(r)]_(s)cycloalkyl, which maybe optionally substituted with one or more R₂₀'s;

or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p)═O; (q)—(C₂-C₆)-alkynyl; (r) —COR₂₆; (s) —S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u)—COOR₂₆; (v) —NHC(CN)NHR₂₆; (w) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (x) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (y) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s) cycloalkyl; (t)cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w) —SO₂NHR₂₆; (x)—COOR₂₆; or (y) —NHC(CN)NHR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆;        and 23) cycloalkyl, which may be optionally substituted with one        or more R₄₀'s;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl,        which may be optionally substituted with one or more R₄₀'s;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)        —NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally        substituted with one or more R₄₀'s;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)        —NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally        substituted with one or more R₄₀'s;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26) cycloalkyl,        which may be optionally substituted with one or more R₄₀'s;    -   (f) hydrogen;    -   (g) alkynyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₄₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (h) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₄₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₄₀'s;        or two R₂₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₄₀'s;

R₂₉ and R₃₀ are independently hydrogen, —[(C═O)O_(r)]_(s)aryl,[(C═O)O_(r)]_(s)alkenyl, —[(C═O)O_(r)]_(s)alkyl, heterocyclyl,—CONR₄₆R₄₆, alkynyl, —COR₃₆, S(O)_(p)R₃₆, —SO₂NHR₃₆, —COOR₃₆,—C(CN)NHR₃₆, or cycloalkyl, wherein the aryl, alkyl, alkenyl, cycloalkylor heterocyclyl may be optionally substituted with one or more R₄'s;

or R₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl, wherein the alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionallysubstituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉,—S(O)_(p)R₄₉, —SO₂NHR₄₉, COOR₄₉, or —NHC(CN)NHR₄₉;

R₄₉ and R₅₀, at each occurrence, are independently hydrogen, alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl, other than heteroaryl;

r is 0 to 5;

s is 0 to 4; and

p is 1 or 2.

In one embodiment, compounds of the present invention are providedwherein the compounds are compounds of formula Ia

In another embodiment, compounds of the present invention are providedwherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)—S(O)_(p)R₆, 18) —SO₂NHR₆, 19) —COOR₆, 20) —NHC(CN)NHR₆, 21) —CONR₆R₆,22) (C₂-C₆)-alkynyl, which may be optionally substituted with one ormore R₂₀'s, 23) (C₂-C₆)-alkenyl, which may be optionally substitutedwith one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆, or 26) —OCONR₆R₆; orany two adjacent substituents may join together to form a 4- to8-membered ring, which optionally may contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R₂₀'s;

B is:

-   -   (a) phenyl, which is substituted with one or more substituents        selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COOR₆, 19) —NHC(CN)NHR₆, and 20) —CONR₆R₆; or    -   (b) heteroaryl, which is substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COOR₆, 19) —NHC(CN)NHR₆, and 20) —CONR₆R₆;

C is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)₆R₆, 15)        —SO₂NHR₆, 16) —COOR₆, and 17) —NHC(CN)NHR₆;    -   (b) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, and 14)        halo(C₁-C₆)alkyl; or    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)₆R₆, 15)        —SO₂NHR₆, 16) —COOR₆, and 17) —NHC(CN)NHR₆;

R₁ is H, —C(O)R₃, —C(O)NR₂R₃, —C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₈, or—C(S)R₃;

R₂ is:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17)        —SO₂NHR₆, 18) —COR₆, and 19) —NHC(CN)NHR₆;    -   (c) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20) —SO₂NHR₆, 21)        —COOR₆, and 22) —NHC(CN)NHR₆; or    -   (d) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂        (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, and 20)        (C₂-C₆)-alkynyl;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)        —COOR₆, and 19) —NHC(CN)NHR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)        —S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; or    -   (f) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20) —SO₂NHR₆, 21)        —COOR₆, and 22) —NHC(CN)NHR₆;        or R₂ and R₃ are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₄ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22)        —COOR₆, and 23) —NHC(CN)NHR₆;    -   (d) (C₂-C₆)-alkenyl; or    -   (e) (C₂-C₆)-alkynyl;

R₅ is arylalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆,        or 23) cycloalkyl, which may be optionally substituted with one        or more R₂₀'s;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆;    -   (f) hydrogen;    -   (g) alkynyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (h) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s;        or two R₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₇ is aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆,20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆;

R₈ can independently be:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, 18) —S(O)_(p)R₂₆, 19)        —SO₂NHR₂₆, 20) —COOR₂₆, and 21) —NHC(CN)NHR₂₆;    -   (c) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆;    -   (d) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆;    -   (e) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆, 21)        —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆; or    -   (f) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20)        —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆;        or two R₈'s are taken together to form a 3- to 9-membered ring,        which may optionally contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₂₀'s;

R₉ and R₁₀ are independently: (a) hydrogen; (b) —[(C═O)O_(r)]_(s)aryl,wherein the aryl may be optionally substituted with one or more R₂₀'s;(c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may beoptionally substituted with one or more R₂₀'s; (d)[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; (e) heterocyclyl optionallysubstituted with one or more R₂₀'s; (f) —CONR₂₆R₂₆; (g)—(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j) —SO₂NHR₂₆; (k)—COOR₂₆; or (l) —NHC(CN)NHR₂₆;

or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p) ═O; (q)—(C₂-C₆)-alkynyl; (r) —COR₂₆; (s) —S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u)—COOR₂₆; (v) —NHC(CN)NHR₂₆; (w) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (x) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (y) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s) cycloalkyl; (t)cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w) —SO₂NHR₂₆; (x)—COOR₂₆; or (y) —NHC(CN)NHR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆;    -   (f) hydrogen;    -   (g) alkynyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₄₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₂₀'s; or    -   (h) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        heteroaryl, which may be optionally substituted with one or more        R₄₀'s, 11) heterocyclyl, which may be optionally substituted        with one or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13)        (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16) ═O, 17)        (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20)        —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl,        which may be optionally substituted with one or more R₄₀'s;        or two R₂₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₄₀'s;

R₂₉ and R₃₀ are independently hydrogen, —[(C═O)O_(r)]_(s)aryl,[(C═O)O_(r)]_(s)alkenyl, —[(C═O)O_(r)]_(s)alkyl, heterocyclyl,—CONR₄₆R₄₆, alkynyl, —COR₃₆, S(O)_(p)R₃₆, —SO₂NHR₃₆, —COOR₃₆, or—C(CN)NHR₃₆, wherein the aryl, alkyl, alkenyl or heterocyclyl may beoptionally substituted with one or more R₄₀'s;

or R₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl, wherein the alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionallysubstituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉,—S(O)_(p)R₄₉, —SO₂NHR₄₉, COOR₄₉, or —NHC(CN)NHR₄₉;

R₄₉ and R₅₀, at each occurrence, are independently hydrogen, alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl, other than heteroaryl;

r is 0 to 5;

is 0 to 4; and

p is 1 or 2.

In yet another embodiment, compounds of the present invention areprovided wherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)—COR₆, 18) —CONR₆R₆, 19) (C₂-C₆)-alkynyl, which may be optionallysubstituted with one or more R₂₀'s, 20) (C₂-C₆)-alkenyl, which may beoptionally substituted with one or more R₂₀'s, 21) —OCOR₆, 22) —OCOOR₆,or 23) —OCONR₆R₆; or any two adjacent substituents may join together toform a 4- to 8-membered ring, which optionally may contain 1-4heteroatoms selected from N, O, and S and be optionally substituted withone or more R₂₀'s;

B is:

-   -   (a) phenyl, which is substituted with one or more substituents        selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COR₆, 16) —COOR₆, and 17) —CONR₆R₆; or    -   (b) a nitrogen containing heteroaryl, which is substituted with        one or more substituents selected from the group consisting        of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —COOR₆,        and 17) —CONR₆R₆;

C is alkyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OR₆, 3) —NR₉R₁₀, 4) aryl,which may be optionally substituted with one or more R₂₀'s, 5)heteroaryl, which may be optionally substituted with one or more R₂₀'s,6) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 7) —CONR₆R₆, and 8) —COOR₆;

R₁ is —C(O)R₃, —C(O)NR₂R₃, —C(O)OR₄ or CH₂R₅;

R₂ is:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —OR₆, 13) —CONR₆R₆, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, and 16) COOR₆;    -   (c) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —OR₆, and 19) —COOR₆; or    -   (d) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂        (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, and 20)        (C₂-C₆)-alkynyl;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which        may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —OR₆, and 20)        —COOR₆; or    -   (f) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —OR₆, and 19) —COOR₆;        or R₂ and R₃ are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₄ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆; or    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;        or two R₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20)        —COOR₂₆;        or two R₈'s are taken together to form a 3- to 9-membered ring,        which may optionally contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₉ and R₁₀ are independently: (a) hydrogen; (b) —[(C═O)O_(r)]_(s)aryl,wherein the aryl may be optionally substituted with one or more R₂₀'s;(c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; or (d) heterocyclyl optionallysubstituted with one or more R₂₀'s;

or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano, (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl;(q) —COR₂₆; (r) —COOR₂₆; (s) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (t) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (u) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl; (s)cycloalkylalkyl; (t) —OR₂₆; or (u) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;        or two R₂₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₄₀'s;

R₂₉ and R₃₀ are independently hydrogen, —[(C═O)O_(r)]_(s)aryl,—[(C═O)O_(r)]_(s)alkyl, or heterocyclyl, wherein the aryl, alkyl orheterocyclyl may be optionally substituted with one or more R₄₀'s;

or R₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl, wherein the alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionallysubstituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉ orCOOR₄₉;

R₄₉ and R₅₀, at each occurrence, are independently hydrogen, alkyl,aryl, heteroaryl or heterocyclyl, other than heteroaryl;

r is 0 to 3;

s is 0 to 2; and

p is 1 or 2.

In still yet another embodiment, compounds of the present invention areprovided wherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)—COR₆, 18) —CONR₆R₆, 19) (C₂-C₆)-alkynyl, which may be optionallysubstituted with one or more R₂₀'s, 20) —OCOR₆, 21) —OCOOR₆, or 22)—OCONR₆R₆; or any two adjacent substituents may join together to form a4- to 8-membered ring, which optionally may contain 1-4 heteroatomsselected from N, O, and S and be optionally substituted with one or moreR₂₀'s;

B is:

-   -   (a) phenyl, which is substituted with one or more substituents        selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —COOR₆, and 16) —CONR₆R₆; or    -   (b) a 6- to 10-membered nitrogen containing heteroaryl, which is        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, and 16)        —CONR₆R₆;

C is alkyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OR₆, 3) —NR₉R₁₀, 4) aryl,which may be optionally substituted with one or more R₂₀'s, 5) anitrogen containing heteroaryl, which may be optionally substituted withone or more R₂₀'s, 6) —CONR₆R₆, and 7) —COOR₆;

R₁ is —C(O)R₃, —C(O)NR₂R₃ or —CH₂R₈;

R₂ is:

-   -   (a) H;    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, and 16) —COOR₆; or    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂        (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, and 20)        (C₂-C₆)-alkynyl;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which        may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and        20)-—COOR₆; or    -   (f) alkenyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17)        (C₂-C₆)-alkynyl, 18) —OR₆, and 19) —COOR₆;        or R₂ and R₃ are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;        or two R₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20)        —COOR₂₆;        or two R₈'s are taken together to form a 3- to 9-membered ring,        which may optionally contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₉ and R₁₀ are independently: (a) hydrogen, (b) —[(C═O)O_(r)]_(s)aryl,wherein the aryl may be optionally substituted with one or more R₂₀'s,or (c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may beoptionally substituted with one or more R₂₀'s;

or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl;(q) —COR₂₆; (r) —COOR₂₆; (s) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (t) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (u) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl; (s)cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;        or two R₂₆'s are taken together to form a 3- to 9-membered ring,        which optionally may contain 1-4 heteroatoms selected from N, O,        and S and be optionally substituted with one or more R₄₀'s;

R₂₉ and R₃₀ are independently hydrogen, —[(C═O)O_(r)]_(s)aryl, or[(C═O)O_(r)]_(s)alkyl, wherein the aryl or alkyl may be optionallysubstituted with one or more R₄₀'s;

or R₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl, wherein the alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionallysubstituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉ or—COR₄₉;

R₄₉ and R₅₀, at each occurrence, are independently hydrogen, alkyl, arylor heteroaryl;

r is 0 to 2;

s is 0 to 1; and

p is 1 or 2.

In one embodiment, compounds of the present invention are providedwherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O,17)-—COOR₆, 18) (C₂-C₆)-alkynyl, which may be optionally substitutedwith one or more R₂₀'s, 19) —OCOR₆, and 20) —OCOOR₆; or any two adjacentsubstituents may join together to form a 4- to 8-membered ring, whichoptionally may contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₂₀'s;

B is:

-   -   (a) phenyl, which is substituted with one or more substituents        selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, and 15) —COOR₆; or    -   (b) a 6-membered nitrogen containing heteroaryl, which is        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, and 15) —COOR₆;

C is alkyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) phenyl, which may beoptionally substituted with one or more R₂₀'s, or 3) a 5- or 6-memberednitrogen containing heteroaryl, which may be optionally substituted withone or more R₂₀'s;

R₁ is —C(O)R₃, —C(O)NR₂R₃ or CH₂R₈;

R₂ is:

-   -   (a) H; or    -   (b) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, and 16) COOR₆;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, and 16) COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which        may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)        —COOR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20)        —COOR₂₆;        or two R₈'s are taken together to form a 3- to 9-membered ring,        which may optionally contain 1-4 heteroatoms selected from N, O,        and S and may be optionally substituted with one or more R₂₀'s;

R₉ and R₁₀ are independently: (a) hydrogen, or (b)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s;

or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl;(q) —COR₂₆; (r) —COOR₂₆; (s) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (t) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (u) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl; (s)cycloalkylalkyl; (t) —OR₂₆; or (u) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;

R₂₉ and R₃₀ are independently hydrogen or —[(C═O)O_(r)]_(s)alkyl,wherein the alkyl may be optionally substituted with one or more R₄₀'s;

or R₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl, wherein the alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl may be optionallysubstituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉, or—COOR₄₉;

R₄₉ and R₅₀, at each occurrence, are independently hydrogen, alkyl,aryl, or heteroaryl;

r is 0 to 2;

s is 0 to 1; and

p is 1 or 2.

In another embodiment, compounds of the present invention are providedwherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)(C₂-C₆)-alkynyl, which may be optionally substituted with one or moreR₂₀'s, and 18) —OCOR₆; or any two adjacent substituents may jointogether to form a 4- to 8-membered ring, which optionally may contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s;

B is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl;

C is alkyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) phenyl, which may be optionallysubstituted with one or more R₂₀'s, or 2) a 5- or 6-membered nitrogencontaining heteroaryl, which may be optionally substituted with one ormore R₂₀'s;

R₁ is —C(O)R₃, —C(O)NHR₃ or —CH₂R₈;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, and 16) COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which        may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) —(C₂-C₆)-alkynyl, 19) —COR₆,        and 20) —COOR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted        with one or more R₂₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₂₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₂₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9)        aryl, which may be optionally substituted with one or more        R₂₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, which may be optionally substituted with one or        more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be        optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20)        —COOR₂₆;

R₉ and R₁₀ are independently: (a) hydrogen; or (b)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which may be optionally substitutedwith one or more R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f)nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionally substituted withone or more R₂₁'s; (i) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (k) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (m)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl;(q) —COR₂₆; (r) —COOR₂₆; (s) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; (t) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s; or (u) —CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl; (s)cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 11) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with        one or more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)        nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted        with one or more R₄₀'s, 10) arylalkyl, which may be optionally        substituted with one or more R₄₀'s, 11) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)        —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally        substituted with one or more R₄₀'s, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)        —NHC(CN)NHR₃₆;    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which        may be optionally substituted with one or more R₄₀'s, 4)        —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9)        aryl, which may be optionally substituted with one or more        R₄₀'s, 10) arylalkyl, which may be optionally substituted with        one or more R₄₀'s, 11) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 12) heteroarylalkyl, which        may be optionally substituted with one or more R₄₀'s, 13)        heterocyclyl, which may be optionally substituted with one or        more R₄₀'s, 14) heterocyclylalkyl, which may be optionally        substituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)        (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20)        (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23)        —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or    -   (f) hydrogen;

R₂₉ and R₃₀ are independently hydrogen or —[(C═O)O_(r)]_(s)alkyl,wherein the alkyl may be optionally substituted with one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl, heteroaryl orheterocyclyl, other than heteroaryl, wherein the alkyl, aryl, heteroarylor heterocyclyl may be optionally substituted with one or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,haloalkyl, haloalkyloxy, alkenyl, arylalkyloxy, ═O, alkynyl, cycloalkylor cycloalkylalkyl;

r is 0 to 2;

s is 0 to 1; and

p is 1 or 2.

In yet another embodiment, compounds of the present invention areprovided wherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, and 17)—OCOR₆; or any two adjacent substituents may join together to form a 4-to 8-membered ring, which optionally may contain 1-4 heteroatomsselected from N, O, and S and be optionally substituted with one or moreR₂₀'s;

B is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl;

C is methyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) phenyl, which may be optionallysubstituted with one or more R₂₀'s, or 2) a 5- or 6-membered nitrogencontaining heteroaryl, which may be optionally substituted with one ormore R₂₀'s;

R₁ is —C(O)R₃, —C(O)NHR₃ or CH₂R₈;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)        (C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally        substituted with one or more R₂₀'s, 9) arylalkyl, which may be        optionally substituted with one or more R₂₀'s, 10) heteroaryl,        which may be optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally        substituted with one or more R₂₀'s, 9) arylalkyl, which may be        optionally substituted with one or more R₂₀'s, 10) heteroaryl,        which may be optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18)        (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which        may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)        (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)        —COOR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11) heterocyclyl,        which may be optionally substituted with one or more R₂₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —SO₂NHR₃₆, 20) —COOR₃₆, and 21) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally        substituted with one or more R₂₀'s, 10) arylalkyl, which may be        optionally substituted with one or more R₂₀'s, 11) heteroaryl,        which may be optionally substituted with one or more R₂₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —SO₂NHR₃₆, 22) —COOR₃₆, and 23)        —NHC(CN)NHR₃₆;    -   (c) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl,        which may be optionally substituted with one or more R₂₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; or    -   (d) hydrogen;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)        aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16)        (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally        substituted with one or more R₂₀'s, 9) arylalkyl, which may be        optionally substituted with one or more R₂₀'s, 10) heteroaryl,        which may be optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally        substituted with one or more R₂₀'s, 9) arylalkyl, which may be        optionally substituted with one or more R₂₀'s, 10) heteroaryl,        which may be optionally substituted with one or more R₂₀'s, 11)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 13) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 14)        halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17)        ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,        which may be optionally substituted with one or more R₂₀'s, 9)        arylalkyl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroaryl, which may be optionally substituted with        one or more R₂₀'s, 11) heteroarylalkyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 13)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)        —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20)        —COOR₂₆;

R₉ and R₁₀ are independently: (a) hydrogen; or (b)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl, which may be optionallysubstituted with one or more R₂₁'s; (i) arylalkyl, which may beoptionally substituted with one or more R₂₁'s; (j) heteroaryl, which maybe optionally substituted with one or more R₂₁'s; (k) heteroarylalkyl,which may be optionally substituted with one or more R₂₁'s; (l)heterocyclyl, which may be optionally substituted with one or moreR₂₁'s; (in) heterocyclylalkyl, which may be optionally substituted withone or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o) (C₂-C₆)-alkenyl; (p)—(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COR₂₆; (s) cycloalkyl, which may beoptionally substituted with one or more R₂₁'s; (t) cycloalkylalkyl,which may be optionally substituted with one or more R₂₁'s; or (u)—CONR₂₆R₂₆;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl; (i) arylalkyl; (j)heteroaryl; (k) heteroarylalkyl; (l) heterocyclyl; (m)heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o) —CONR₂₆R₂₆; (p)(C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl; (s)cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally        substituted with one or more R₄₀'s, 10) heteroaryl, which may be        optionally substituted with one or more R₄₀'s, 11) heterocyclyl,        which may be optionally substituted with one or more R₄₀'s, 12)        halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)        —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)        —SO₂NHR₃₆, 20) —COOR₃₆, and 21) —NHC(CN)NHR₃₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally        substituted with one or more R₄₀'s, 10) arylalkyl, which may be        optionally substituted with one or more R₄₀'s, 11) heteroaryl,        which may be optionally substituted with one or more R₄₀'s, 12)        heteroarylalkyl, which may be optionally substituted with one or        more R₄₀'s, 13) heterocyclyl, which may be optionally        substituted with one or more R₄₀'s, 14) heterocyclylalkyl, which        may be optionally substituted with one or more R₄₀'s, 15)        halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═, 19)        (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —SO₂NHR₃₆, 22) —COOR₃₆, and 23)        —NHC(CN)NHR₃₆;    -   (c) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)        (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl,        which may be optionally substituted with one or more R₄₀'s, 10)        arylalkyl, which may be optionally substituted with one or more        R₄₀'s, 11) heteroaryl, which may be optionally substituted with        one or more R₄₀'s, 12) heteroarylalkyl, which may be optionally        substituted with one or more R₄₀'s, 13) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 14)        heterocyclylalkyl, which may be optionally substituted with one        or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)        —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21)        —COR₃₆, 22) —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; or    -   (d) hydrogen;

R₂₉ and R₃₀ are independently hydrogen or —[(C═O)O_(r)]_(s)alkyl,wherein the alkyl may be optionally substituted with one or more R₄₀'s;

R₃₆, at each occurrence, is independently alkyl, aryl or heteroaryl,wherein the alkyl, aryl or heteroaryl may be optionally substituted withone or more R₄₀'s;

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,haloalkyl, haloalkyloxy, alkenyl, arylalkyloxy, ═O, alkynyl, cycloalkyl,or cycloalkylalkyl;

r is 0 to 2; and

s is 0 to 1.

In still yet another embodiment, compounds of the present invention areprovided wherein:

A is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, and 15) —COR₆;

B is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl;

C is methyl, which is substituted with a 5- or 6-membered nitrogencontaining heteroaryl, which may be optionally substituted with one ormore R₂₀'s;

R₁ is —C(O)R₃, —C(O)NHR₃ or CH₂R₈;

R₃ is:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) aryl, which may be optionally substituted with one or        more R₂₀'s, 8) heteroaryl, which may be optionally substituted        with one or more R₂₀'s, 9) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 10) halo(C₁-C₆)alkyl, 11)        (C₂-C₆)-alkenyl, 12) (C₂-C₆)-alkynyl, 13) —COR₆, and 14) —COR₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) aryl, which may be optionally substituted with one or        more R₂₀'s, 8) arylalkyl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 11)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —OR₆, and 17) —COOR₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) aryl, which may be optionally substituted        with one or more R₂₀'s, 8) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 9) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 10)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 11) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16)        —OR₆, and 17) —COOR₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) aryl, which may be optionally substituted        with one or more R₂₀'s, 8) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 9) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 10)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 11) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16)        —COR₆, and 17) —COOR₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)        (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) aryl, which may be        optionally substituted with one or more R₂₀'s, 8) arylalkyl,        which may be optionally substituted with one or more R₂₀'s, 9)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroarylalkyl, which may be optionally substituted        with one or more R₂₀'s, 11) heterocyclyl, which may be        optionally substituted with one or more R₂₀'s, 12)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)        (C₂-C₆)-alkynyl, 16) —COR₆, and 17) —COOR₆;

R₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) aryl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₂₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) —COOH, 14)        (C₂-C₆)-alkynyl, 15) —COR₃₆, and 16) —COOR₃₆; or    -   (b) hydrogen;

R₈ can independently be:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) aryl, which may be optionally substituted with one or        more R₂₀'s, 8) heteroaryl, which may be optionally substituted        with one or more R₂₀'s, 9) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 10) halo(C₁-C₆)alkyl, 11)        (C₂-C₆)-alkenyl, 12) (C₂-C₆)-alkynyl, 13) —COR₂₆, and 14)        —COOR₂₆;    -   (b) aryl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)        nitro, 7) aryl, which may be optionally substituted with one or        more R₂₀'s, 8) arylalkyl, which may be optionally substituted        with one or more R₂₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₂₀'s, 10) heteroarylalkyl, which        may be optionally substituted with one or more R₂₀'s, 11)        heterocyclyl, which may be optionally substituted with one or        more R₂₀'s, 12) heterocyclylalkyl, which may be optionally        substituted with one or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14)        (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —COR₂₆, and 17)        —COOR₂₆;    -   (c) cycloalkyl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) aryl, which may be optionally substituted        with one or more R₂₀'s, 8) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 9) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 10)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 11) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16)        —COR₂₆, and 17) —COOR₂₆;    -   (d) heteroaryl, which may be optionally substituted with one or        more substituents selected from the group consisting of: 1)        halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)        cyano, 6) nitro, 7) aryl, which may be optionally substituted        with one or more R₂₀'s, 8) arylalkyl, which may be optionally        substituted with one or more R₂₀'s, 9) heteroaryl, which may be        optionally substituted with one or more R₂₀'s, 10)        heteroarylalkyl, which may be optionally substituted with one or        more R₂₀'s, 11) heterocyclyl, which may be optionally        substituted with one or more R₂₀'s, 12) heterocyclylalkyl, which        may be optionally substituted with one or more R₂₀'s, 13)        halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16)        —COR₂₆, and 17) —COOR₂₆; or    -   (e) heterocyclyl, other than heteroaryl, which may be optionally        substituted with one or more substituents selected from the        group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)        (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be        optionally substituted with one or more R₂₀'s, 8) arylalkyl,        which may be optionally substituted with one or more R₂₀'s, 9)        heteroaryl, which may be optionally substituted with one or more        R₂₀'s, 10) heteroarylalkyl, which may be optionally substituted        with one or more R₂₀'s, 11) heterocyclyl, which may be        optionally substituted with one or more R₂₀'s, 12)        heterocyclylalkyl, which may be optionally substituted with one        or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)        (C₂-C₆)-alkynyl, 16) —COR₂₆, and 17) —COR₂₆;

R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) aryl, which may be optionally substituted withone or more R₂₁'s; (h) arylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (i) heteroaryl, which may be optionallysubstituted with one or more R₂₁'s; (j) heteroarylalkyl, which may beoptionally substituted with one or more R₂₁'s; (k) heterocyclyl, whichmay be optionally substituted with one or more R₂₁'s; (l)heterocyclylalkyl, which may be optionally substituted with one or moreR₂₁'s; (m) halo(C₁-C₆)alkyl; (n) (C₂-C₆)-alkenyl; (o) —(C₂-C₆)-alkynyl;(p) —COR₂₆; (q) —COOR₂₆; (r) cycloalkyl, which may be optionallysubstituted with one or more R₂₁'s; or (s) cycloalkylalkyl, which may beoptionally substituted with one or more R₂₁'s;

R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio;(e) cyano; (f) nitro; (g) aryl; (h) arylalkyl; (i) heteroaryl; (j)heteroarylalkyl; (k) heterocyclyl; (l) heterocyclylalkyl; (m)halo(C₁-C₆)alkyl; (n) (C₂-C₆)-alkenyl; (o) (C₂-C₆)-alkynyl; (p)cycloalkyl; (q) cycloalkylalkyl; (r) —COR₂₆; or (s) —COOR₂₆;

R₂₆, at each occurrence, is independently:

-   -   (a) alkyl, which may be optionally substituted with one or more        substituents selected from the group consisting of: 1) halo, 2)        —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6)        cyano, 7) nitro, 8) aryl, which may be optionally substituted        with one or more R₄₀'s, 9) heteroaryl, which may be optionally        substituted with one or more R₄₀'s, 10) heterocyclyl, which may        be optionally substituted with one or more R₄₀'s, 11)        halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) —COOH, 14)        (C₂-C₆)-alkynyl, 15) —COR₃₆, or 16) —COOR₃₆; or    -   (b) hydrogen;

R₃₆, at each occurrence, is independently alkyl, aryl or heteroaryl,wherein the alkyl, aryl or heteroaryl may be optionally substituted withone or more R₄₀'s; and

R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,haloalkyl, haloalkyloxy, alkenyl, arylalkyloxy, alkynyl, cycloalkyl orcycloalkylalkyl.

Also in accordance with the present invention, compounds of the presentinvention are those wherein:

A is:

B is:

C is:

R₁ is:

(a) —C(O)R₃, wherein R₃:

(b) —C(O)NHR₃, wherein the R₃ is:

(c) —C(O)NR₂R₃, wherein dthe NR₂R₃ is:

(d) —C(O)OR₄ wherein the R₄ is:

(e) —SO₂R₅ wherein the R₅ is:

(f) —CSNHR₇ wherein the R₇ is:

(g) —CH₂R₈ wherein the R₈ is:

(h) —C(S)R₃ wherein the R₃ is:

(i) —C(═NR₃)Oalkyl wherein the R₃ is:

Also in accordance with the present invention, compounds of the presentinvention are those wherein:

A is:

B is:

C is:

R₁ is H or:

(a) —C(O)R₃, wherein R₃:

(b) —C(O)NHR₃, wherein the R₃ is:

(c) —C(O)NR₂R₃, wherein the NR₂R₃ is:

(d) —C(O)OR₄ wherein the R₄ is:

(e) —SO₂R₅ wherein the R₅ is:

(f) —CSNHR₇ wherein the R₇ is:

(g) —CH₂R₈ wherein the R₈ is:

(h) —C(S)R₃, wherein R₃:

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in the examples, for example, Examples273, 293, 305, and 337.

In yet another embodiment, pharmaceutical compositions comprised ofcompounds of the present invention alone or in combination with apharmaceutically acceptable carrier and/or at least one additionaltherapeutic agent.

In still yet another embodiment, methods of inhibiting the cholesterylester transfer protein comprising administering to a mammal in need oftreatment a compound and/or pharmaceutical composition of the presentinvention are provided.

In one embodiment, methods for treating, preventing or slowing theprogression of Alzheimer's, atherosclerosis, venous thrombosis, coronaryartery disease, coronary heart disease, coronary vascular disease,peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal (including a human beingeither male or female) by administering to a mammal in need of suchtreatment an atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia treating, preventing or slowing amountof a compound and/or pharmaceutical composition of the present inventionare provided.

In another embodiment, methods for treating, preventing or slowing theprogression of atherosclerosis in a mammal by administering to a mammalin need of such treatment an atherosclerotic treating, preventing orslowing amount of a compound and/or pharmaceutical composition of thepresent invention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of peripheral vascular disease in a mammal by administeringto a mammal in need of such treatment a peripheral vascular diseasetreating, preventing or slowing amount of a compound and/orpharmaceutical composition of the present invention are provided.

In yet another embodiment, methods for treating, preventing or slowingthe progression of dyslipidemia in a mammal by administering to a mammalin need of such treatment a dyslipidemia treating, preventing or slowingamount of a compound and/or pharmaceutical composition of the presentinvention are provided.

In still yet another embodiment, methods for treating, preventing orslowing the progression of hyperbetalipoproteinemia in a mammal byadministering to a mammal in need of such treatment ahyperbetalipoproteinemia treating, preventing or slowing amount of acompound and/or pharmaceutical composition of the present invention areprovided.

In one embodiment, methods for treating, preventing or slowing theprogression of hypoalphalipoproteinemia in a mammal by administering toa mammal in need of such treatment a hypoalphalipoproteinemia treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of hypercholesterolemia in a mammal by administering to amammal in need of such treatment a hypercholesterolemia treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In yet another embodiment, methods for treating, preventing or slowingthe progression of hypertriglyceridemia in a mammal by administering toa mammal in need of such treatment a hypertriglyceridemia treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In still yet another embodiment, methods for treating, preventing orslowing the progression of familial-hypercholesterolemia in a mammal byadministering to a mammal in need of such treatment afamilial-hypercholesterolemia treating, preventing or slowing amount ofa compound and/or pharmaceutical composition of the present inventionare provided.

In one embodiment, methods for treating, preventing or slowing theprogression of cardiovascular disorders in a mammal by administering toa mammal in need of such treatment a cardiovascular disorder treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of angina in a mammal by administering to a mammal in needof such treatment an angina treating, preventing or slowing amount of acompound and/or pharmaceutical composition of the present invention areprovided.

In yet another embodiment, methods for treating, preventing or slowingthe progression of ischemia in a mammal by administering to a mammal inneed of such treatment an ischemic disease treating, preventing orslowing amount of a compound and/or pharmaceutical composition of thepresent invention are provided.

In still yet another embodiment, methods for treating, preventing orslowing the progression of cardiac ischemia in a mammal by administeringto a mammal in need of such treatment a cardiac ischemic treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In one embodiment, methods for treating, preventing or slowing theprogression of stroke in a mammal by administering to a mammal in needof such treatment a stroke treating, preventing or slowing amount of acompound and/or pharmaceutical composition of the present invention areprovided.

In one embodiment, methods for treating, preventing or slowing theprogression of a myocardial infarction in a mammal by administering to amammal in need of such treatment a myocardial infarction treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of reperfusion injury in a mammal by administering to amammal in need of such treatment a reperfusion injury treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of angioplastic restenosis in a mammal by administering to amammal in need of such treatment an angioplastic restenosis treating,preventing or slowing amount of a compound and/or pharmaceuticalcomposition of the present invention are provided.

In yet another embodiment, methods for treating, preventing or slowingthe progression of hypertension in a mammal by administering to a mammalin need of such treatment a hypertension treating, preventing or slowingamount of a compound and/or pharmaceutical composition of the presentinvention are provided.

In yet another embodiment, methods for treating, preventing or slowingthe progression of the ascular complications of diabetes in a mammal byadministering to a mammal in need of such treatment a vascularcomplications of diabetes treating, preventing or slowing amount of acompound and/or pharmaceutical composition of the present invention areprovided.

In still yet another embodiment, methods for treating, preventing orslowing the progression of obesity in a mammal by administering to amammal in need of such treatment an obesity treating, preventing orslowing amount of a compound and/or pharmaceutical composition of thepresent invention are provided.

In one embodiment, methods for treating, preventing or slowing theprogression of endotoxemia in a mammal by administering to a mammal inneed of such treatment an endotoxemia treating, preventing or slowingamount of a compound and/or pharmaceutical composition of the presentinvention are provided.

In another embodiment, methods for treating, preventing or slowing theprogression of a disease requiring cholesteryl ester transfer proteininhibitor therapy comprising administering, concurrently orsequentially, to a mammal in need of treatment, prevention or slowing atherapeutically effective amount of a compound of the present inventionand at least one additional therapeutic agent.

In yet another embodiment, methods of inhibiting remnant lipoproteinproduction comprising administering to a mammal a compound and/orpharmaceutical composition of the present invention are provided.

In still yet another embodiment, methods of raising HDL cholesterol in amammal comprising administering to a mammal in need of treatment acompound and/or pharmaceutical composition of the present invention areprovided.

Mono fluorinated phenols have been widely used as synthetic blocks formany bioactive compounds. To date, there have been several methodsreported in the literature for the synthesis of such phenols. Forexample, such phenols may be prepared by: (i) electrophilic fluorinationof phenols using a range of F⁺ reagents; (ii) hydrolysis ofbromofluorobenzene or chlorofluorobenzene catalysized by a copperreagent; (iii) diazotization of a corresponding fluoroaniline; (iv)selective hydroxy substitution of difluorobenzoic acid with solid sodiumhydroxide in 1,3-dimethyl-2-imidazolidinone (see, Journal of FluorineChemistry, 121:97-99 (2003) and Bioorganic & Medicinal Chemistry,12:5661-5675 (2004)); and (iv) the replacement of fluoroatom ofactivated arylfluorides such as fluoroanthracene-9,10-diones,fluorobenz[g]isoquinoline-5,10-diones and fluoronitrobenzenes withsodium trimethylsilanoate in specific solvent THF (see SyntheticCommunications, 28(18):3415-3422). However, most of these methods usereagents that unsafe, highly hazardous and/or not readily available. Inaddition, these methods may only be suitable for the synthesis of 2- or4-fluorophenols, and/or produce the desired compounds in low yields.

Thus, although there are a variety of methods used to produce monofluorinated phenols, there is a continuing need and a continuing searchin this field of art for alternative methods to produce mono fluorinatedphenols under safe conditions and in greater yields.

In one embodiment, processes for the preparation of mainly a compound offormula WW, B—OCF₂CF₂H, comprising reducing a mixture comprised of acompound of formula WW and a compound of formula YY, B—OCF₂CF₂Br, withzinc dust under acidic conditions, wherein B is phenyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)₆R₆,17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20) —CONR₆R₆ and R₆, R₉and R₁₀ are defined as set forth above, are provided.

In one embodiment, processes for the preparation of a mixture comprisedof a compound of formula WW and a compound of formula YY, B—OCF₂CF₂Br,comprising reacting a compound of formula ZZ, B—OH, with1,2-dibromotetrafluoroethane under basic conditions, wherein B isphenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆,16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆ and R₆, R₉ and R₁₀ are defined as set forth above, areprovided.

In one embodiment, processes for the preparation of a compound offormula ZZ comprising reacting a compound of formula AAA, B—F, withpotassium trimethylsilanoate in a solvent other than THF, wherein B isphenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆,16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆ and R₆, R₉ and R₁₀ are defined as set forth above, areprovided.

In another embodiment, processes for the preparation of compound offormula WW, wherein B is phenyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3)-Oalkyl, and 4) cyano, are provided. The presentinventions provides such methods.

In one embodiment, processes for the preparation of mainly a compound offormula WW, wherein the acid is trifluoroacetic acid, acetic acid,formic acid and other acidic solvents known in the art, preferablyacetic acid, are provided.

In another embodiment, processes for the preparation of mainly acompound of formula WW, wherein the step of reducing the mixture of acompound of formula WW and a compound of formula YY to form mainly acompound of formula WW comprises heating the reaction mixture at about50° C. for about one to about 15 hours, preferably for about five (5)hours, are provided.

In yet another one embodiment, processes for the preparation of amixture of a compound of formula WW and a compound of formula YY,wherein the base is sodium hydride, sodium methoxide, potassiummethoxide, potassium carbonate, sodium carbonate, cesium carbonate,lithium carbonate, and ammonium carbonate, preferably cesium carbonate,are provided.

In still yet another embodiment, processes for the preparation of amixture of a compound of formula WW and a compound of formula YY,wherein the step of reacting a compound of formula ZZ with1,2-dibromotetrafluoroethane is carried out in a solvent, are provided.

In another embodiment, processes for the preparation of a mixture of acompound of formula WW and a compound of formula YY, wherein the solventis diglyme, DMSO, DMF or NMP, preferably, DMSO, are provided.

In one embodiment, processes for the preparation of a mixture of acompound of formula WW and a compound of formula YY, wherein the step ofreacting a compound of formula ZZ with 1,2-dibromotetrafluoroethanecomprises heating the reaction mixture at about 50° to about 140° C.,preferably at about 50° C., for about ten (10) minutes to about 15hours, preferably about five (5) hours, are provided.

In another embodiment, processes for the preparation of a compound offormula ZZ, wherein the solvent is diglyme, dioxane, DMF ordiethoxyethane, preferably diglyme or diethoxyethan, are provided.

In yet another embodiment, processes for the preparation of a compoundof formula ZZ, wherein the step of reacting a compound of formula AAAwith potassium trimethylsilanoate in a solvent other than THF comprisesheating the reaction mixture at about 100° to about 140° C., preferablyat about 120° C., for about three (3) hours to about three (3) days,preferably, for about five (5) hours, are provided.

Synthesis

Generally, compounds of the present invention may be prepared by methodssuch as those illustrated in the following Schemes A to W. Exemplarycompounds of the present invention were prepared by the methodsillustrated in the examples set forth below. Solvents, temperatures,pressures, and other reaction conditions may readily be selected by oneof ordinary skill in the art. Starting materials are commerciallyavailable or readily prepared by one of ordinary skill in the art.Combinatorial techniques may be employed in the preparation ofcompounds, for example, where the intermediates possess groups suitablefor these techniques.

As illustrated in Scheme A, a substituted phenyl reagent of Formula II,wherein the composition of A is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula II is a nitrile group or a halogen group, such asbromine, can be combined with a reagent of Formula III, wherein thecomposition of B is as described under Formula Ia & Ib, with therequirement that at least one of the substituents (X) attached to thereagent of Formula III is a halide group, such as bromine, or a nitrilegroup, followed by treatment with a base, such as nBuLi. Alternatively,a substituted phenyl reagent of Formula II, wherein the composition of Ais as described under Formula Ia & Ib, with the requirement that atleast one of the substituents (X) attached to the reagent of Formula IIis an aldehyde group or a halogen group, such as bromine, can becombined with a reagent of Formula III, wherein the composition of B isas described under Formula Ia & Ib, with the requirement that at leastone of the substituents (X) attached to the reagent of Formula III is ahalide group, such as bromine, or an aldehyde group, followed bytreatment with a base, such as nBuLi, followed by treatment with anoxidizing agent such as, MnO₄ or Jone's Reagent. The resulting mixturecan then be treated with a tri-alkyl silyl halide reagent, such astrimethylsilyl chloride, to yield a trimethylsilyl imide intermediate ofFormula IV. To the imide intermediate of Formula IV can be added a metalhalide (MX) reagent, such as an alkyl lithium complex, a magnesiumbromide complex or a magnesium chloride complex, or a zinc bromide orzinc chloride complex, of Formula V, where the metal halide complex ismade from a reagent wherein the composition of C is as described underFormula Ia & Ib, followed by treatment with acid, such as HCl, to removethe silyl group, to yield the racemic intermediate of Formula VI. Aswill be described in the proceeding schemes, the racemic intermediate ofFormula VI will allow for the generation of compounds of Formula Ia orIb via the routes to be described.

As illustrated in Scheme B, a substituted phenyl reagent of Formula II,wherein the composition of A is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula II is a nitrile group or a halogen group, such asbromine, can be combined with a reagent of Formula III, wherein thecomposition of B is as described under Formula Ia & Ib, with therequirement that at least one of the substituents (X) attached to thereagent of Formula III is a halide group, such as bromine, or a nitrilegroup, followed by treatment with a base, such as nBuLi. Alternatively,a substituted phenyl reagent of Formula II, wherein the composition of Ais as described under Formula Ia & Ib, with the requirement that atleast one of the substituents (X) attached to the reagent of Formula IIis an aldehyde group or a halogen group, such as bromine, can becombined with a reagent of Formula III, wherein the composition of B isas described under Formula Ia & Ib, with the requirement that at leastone of the substituents (X) attached to the reagent of Formula III is ahalide group, such as bromine, or an aldehyde group, followed bytreatment with a base, such as nBuLi, followed by treatment with anoxidizing agent such as, MnO₄ or Jone's Reagent. The resulting mixturecan then be treated with a substituted sulfinamide reagent, such as(R)-4-methylbenzenesulfinamide or (R)-4-methylbenzenesulfinamide or(S)-2-methylpropane-2-sulfinamide or (R)-2-methylpropane-2-sulfinamide,along with Ti(OEt)₄, to yield a the sulfinyl imide intermediate ofFormula VII. To the sulfinyl imide intermediate of Formula VII can beadded a metal halide reagent (MX), such as a magnesium bromide complexor a magnesium chloride complex, or a zinc bromide or zinc chloridecomplex, of Formula V, where the metal halide complex is made from areagent wherein the composition of C is as described under Formula Ia &Ib, with or without a Lewis acid, such as BF₃.(Et)₂O, followed bytreatment with acid, such as HCl, to hydrolyze the sulfinamide, to yieldthe intermediates of Formula VIa and VIb. By application of substitutedsulfinamide reagent, such as (R)-4-methylbenzenesulfinamide or(R)-4-methylbenzenesulfinamide or (S)-2-methylpropane-2-sulfinamide or(R)-2-methylpropane-2-sulfinamide one skilled in the art can enrich theformation of the (R) antipode (Formula VIa) versus the (S) antipode(Formula VIb) or the (S) antipode (Formula VIb) versus the (R) antipode(Formula VIa), respectively. As will be described in the proceedingschemes, the intermediate of Formula VIa and VIb will allow for thegeneration of compounds of Formula Ia or Ib via the routes to bedescribed.

As illustrated in Scheme C, a substituted phenyl reagent of Formula II,wherein the composition of A is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula III is an alkyl ester group, such as a methyl oran ethyl ester, can be combined with a reagent of Formula III, whereinthe composition of B is as described under Formula Ia & Ib, with therequirement that at least one of the substituents (X) attached to thereagent of Formula III is a halide group, such as bromine, followed bytreatment with a base, such as nBuLi. The resulting mixture can then betreated with a substituted sulfinamide reagent, such as(R)-4-methylbenzenesulfinamide or (R)-4-methylbenzenesulfinamide or(S)-2-methylpropane-2-sulfinamide or (R)-2-methylpropane-2-sulfinamide,along with Ti(OEt)₄, to yield a the sulfonylimide intermediate ofFormula VII. In addition, as illustrated in Scheme C, a substitutedphenyl reagent of Formula II, wherein the composition of A is asdescribed under Formula Ia & Ib, with the requirement that at least oneof the substituents (X) attached to the reagent of Formula II is ahalide group, such as bromine, can be combined with a reagent of FormulaIII, wherein the composition of B is as described under Formula Ia & Ib,with the requirement that at least one of the substituents (X) attachedto the reagent of Formula III is an alkyl ester group, such as a methylor an ethyl ester, followed by treatment with a base, such as nBuLi. Theresulting mixture can then be treated with a substituted sulfinamidereagent, such as (R)-4-methylbenzenesulfinamide or(R)-4-methylbenzenesulfinamide or (S)-2-methylpropane-2-sulfinamide or(R)-2-methylpropane-2-sulfinamide, along with Ti(OEt)₄, to yield a thesulfinyl imide intermediate of Formula VII. To the sulfinyl imideintermediate of Formula VII can be added a metal halide reagent, such asan alkyl lithium complex, a magnesium bromide or a magnesium chloridecomplex, or a zinc bromide or zinc chloride complex, of Formula V, wherethe metal halide complex is made from a reagent wherein the compositionof C is as described under Formula Ia & Ib, with or without a Lewisacid, such as BF₃.(Et)₂O, followed by treatment with acid, such as HCl,to hydrolyze the sulfinamide, to yield the intermediates of Formula VIaand VIb. By application of substituted sulfinamide reagent, such as(R)-4-methylbenzenesulfinamide or (R)-4-methylbenzenesulfinamide or(S)-2-methylpropane-2-sulfinamide or (R)-2-methylpropane-2-sulfinamideone skilled in the art can enrich the formation of the (R) antipode(Formula VIa) versus the (S) antipode (Formula VIb) or the (S) antipode(Formula VIb) versus the (R) antipode (Formula VIa), respectively. Aswill be described in the proceeding schemes, the intermediate of FormulaVIa and VIb will allow for the generation of compounds of Formula Ia orIb via the routes to be described.

As illustrated in Scheme D, to the sulfinyl imide intermediate ofFormula VII can be added a base, such as LDA or nBuLi, with or with outthe addition of TiCl(iOPr)₃, and a reagent of Formula VIII, wherein thecomposition of C is as described under Formula Ia & Ib, with therequirement that at least one of the substituents attached to thereagent of Formula VIII is a hydrogen that can be deprotonated to yielda reactive anion species, followed by treatment with acid, such as HCl,to hydrolyze the sulfinamide, to yield the intermediates of Formula VIaand VIb. By application of substituted sulfinamide reagent, such as(R)-4-methylbenzenesulfinamide or (R)-4-methylbenzenesulfinamide or(S)-2-methylpropane-2-sulfinamide or (R)-2-methylpropane-2-sulfinamideone skilled in the art can enrich the formation of the (R) antipode(Formula VIa) versus the (S) antipode (Formula VIb) or the (S) antipode(Formula VIb) versus the (R) antipode (Formula VIa), respectively. Aswill be described in the proceeding schemes, the intermediate of FormulaVIa and VIb will allow for the generation of compounds of Formula Ia orIb via the routes to be described.

As illustrated in Scheme E, an advanced intermediate of Formula VIa/bcan be treated with an acylating agent, such as an acid halide ofFormula R₃COX, where X=a halogen, such as chlorine or bromine, or ananhydride of Formula (R₃CO)₂O, with or without the presence of a base,such as triethylamine, pyridine or N-ethyl-N-isopropylpropan-2-amine, togenerate an amide derivative of Formula IX, where R₃ is derived from theafore mentioned acylating agent or anhydride and is as described forFormula Ia and Ib. Alternatively, one can treat an advanced intermediateof Formula VIa/b with a carboxylate intermediate of Formula R₃COOH,along with a coupling agent, such as EDCI, DCC or other agents known toone skilled in the art for facilitating amide bond formation, along withor without a base, such as triethylamine, pyridine orN-ethyl-N-isopropylpropan-2-amine, to generate an amide derivative ofFormula IX, which is a compound of Formula Ia and Ib, where R₃ is asdescribed for Formula Ia and Ib.

As illustrated in Scheme F, an advanced intermediate of Formula VIa/bcan be treated with an isocyanate of Formula R₃NCO, with or without thepresence of a base, such as triethylamine, pyridine orN-ethyl-N-isopropylpropan-2-amine, to generate an urea derivative ofFormula X, where R₃ is derived from the afore mentioned isocyanatereagents and is as described for Formula Ia and Ib. Alternatively, onecan react an advanced intermediate of Formula VIa/b with an agent suchas 4-nitrophenyl carbonochloridate or prop-1-en-2-yl carbonochloridate,to create a reactive carbamate intermediate which can then be reactedwith an amine or amine salt intermediate of Formula R₃NH₂, with orwithout the presence of a base, such as triethylamine, pyridine orN-ethyl-N-isopropylpropan-2-amine, to generate an urea derivative ofFormula X, which is a compound of Formula Ia and Ib, where R₃ is asdescribed for Formula Ia and Ib.

As illustrated in Scheme G, an advanced intermediate of Formula VIa/bcan be treated with a carbonochloridate of Formula R₄OCOCl, in thepresence of a base, such as potassium carbonate, to generate a carbamatederivative of Formula XI, which is a compound of Formula Ia and Ib,where R₄ is derived from the afore mentioned carbonochloridate reagentsand is as described for Formula Ia and Ib.

As illustrated in Scheme H, an advanced intermediate of Formula VIa/bcan be treated with a sulfonyl chloride of Formula R₅SO₂Cl, in thepresence of a base, such as triethylamine, pyridine orN-ethyl-N-isopropylpropan-2-amine, to generate a sulfonamide derivativeof Formula XII, which is a compound of Formula Ia and Ib, where R₅ isderived from the afore mentioned sulfonyl chloride reagents and is asdescribed for Formula Ia and Ib.

As illustrated in Scheme I, an advanced intermediate of Formula VIa/bcan be treated with an aldehyde of Formula R₈CHO, with or without acatalytic amount of an acid, such as acetic acid, followed by treatmentwith a reducing agent, such as NaBH(OAc)₃, to generate an alkyl aminederivative of Formula XIII, which is a compound of Formula Ia and Ib,where R₈ is derived from the afore mentioned aldehyde reagents and is asdescribed for Formula Ia and Ib.

As illustrated in Scheme J, an advanced intermediate of Formula VIa/bcan be treated with ketone of Formula R₈R₈CO, with or without acatalytic amount of an acid, such as acetic acid, followed by treatmentwith a reducing agent, such as NaBH(OAc)₃, to generate an alkyl aminederivative of Formula XIV, which is a compound of Formula Ia and Ib,where R₈ is derived from the afore mentioned ketone reagents and is asdescribed for Formula Ia and Ib.

As illustrated in Scheme K, an advanced intermediate of Formula VIa/bcan be treated with an isothiocyanate of Formula R₃NCS, with or withouta base, such as triethylamine, pyridine orN-ethyl-N-isopropylpropan-2-amine, to generate a thiourea derivative ofFormula XV, which is a compound of Formula Ia and Ib, where R₃ isderived from the afore mentioned isothiocyanate reagents and is asdescribed for Formula Ia and Ib.

As illustrated in Scheme L, an advanced intermediate of Formula VIa/bcan be treated with an oxirane reagent, of Formula CH₂OCHRs, in thepresence of a catalyst, such as Sc(OSO₂CF₃)₃ or Yb(OSO₂CF₃)₃, withstandard heating or via irradiation in a microwave, to generate an alkylhydroxy amine derivative of Formula XVI, which is a compound of FormulaIa and Ib, where R₈ is derived from the afore mentioned oxirane reagentsand is as described for Formula Ia and Ib.

As illustrated in Scheme M, a reagent of Formula X, which is a compoundof Formula Ia and Ib, can be treated with a disubstituted amine reagentof Formula R₂R₃NH, with heating or via irradiation in a microwave, toobtained a disubstituted urea derivative of Formula XVII, which is acompound of Formula Ia and Ib, where R₂ and R₃ is derived from the aforementioned disubstituted amine reagent and is as described for Formula Iaand Ib.

As illustrated in Scheme N, a reagent of Formula IX, which is a compoundof Formula Ia and Ib, can be treated with an agent, such as Lawesson'sreagent or any other reagent known to one skilled in the art forconversion of an amide functional group to a thioamide functional group,to obtained a thioamide derivative of Formula XVIII, which is a compoundof Formula Ia and Ib, where R₃ is derived as described for Formula Iaand Ib.

As illustrated in Scheme O, a substituted phenyl reagent of Formula XIX,wherein the composition of A is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents attached to thereagent of Formula XIX is a N-methoxy-N-methylacetamide group, can becombined with a reagent of Formula III, wherein the composition of B isas described under Formula Ia & Ib, with the requirement that at leastone of the substituents (X) attached to the reagent of Formula III is ahalide group, such as bromine, followed by treatment with a base, suchas nBuLi. The resulting mixture can then be treated with a substitutedsulfinamide reagent, such as (R)-4-methylbenzenesulfinamide or(R)-4-methylbenzenesulfinamide or (S)-2-methylpropane-2-sulfinamide or(R)-2-methylpropane-2-sulfinamide, along with Ti(OEt)₄, to yield a thesulfinyl imide intermediate of Formula VII. To the sulfinyl imideintermediate of Formula VII can be added a metal halide reagent (MX),such as a magnesium bromide complex or a magnesium chloride complex, ora zinc bromide or zinc chloride complex, of Formula V, where the metalhalide complex is made from a reagent wherein the composition of C is asdescribed under Formula Ia & Ib, with or without a Lewis acid, such asBF₃.(Et)₂O, followed by treatment with acid, such as HCl, to hydrolyzethe sulfinamide, to yield the penultimate intermediates of Formula VIaand VIb. In addition, a substituted phenyl reagent of Formula II,wherein the composition of A is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents attached to thereagent of Formula II is a halide group, such as bromine, can becombined with a reagent of Formula XX, wherein the composition of B isas described under Formula Ia & Ib, with the requirement that at leastone of the substituents (X) attached to the reagent of Formula XX, is aN-methoxy-N-methylacetamide group, followed by treatment with a base,such as nBuLi. The resulting mixture can then be treated with asubstituted sulfinamide reagent, such as (R)-4-methylbenzenesulfinamideor (R)-4-methylbenzenesulfinamide or (S)-2-methylpropane-2-sulfinamideor (R)-2-methylpropane-2-sulfinamide, along with Ti(OEt)₄, to yield athe sulfinyl imide intermediate of Formula VII. To the sulfinyl imideintermediate of Formula VII can be added a metal halide reagent (MX),such as a magnesium bromide complex or a magnesium chloride complex, ora zinc bromide or zinc chloride complex, of Formula V, where the metalhalide complex is made from a reagent wherein the composition of C is asdescribed under Formula Ia & Ib, with or without a Lewis acid, such asBF₃.(Et)₂O, followed by treatment with acid, such as HCl, to hydrolyzethe sulfinamide, to yield the penultimate intermediates of Formula VIaand VIb. By application of substituted sulfinamide reagent, such as(R)-4-methylbenzenesulfinamide or (R)-4-methylbenzenesulfinamide or(S)-2-methylpropane-2-sulfinamide or (R)-2-methylpropane-2-sulfinamideone skilled in the art can enrich the formation of the (R) antipode(Formula VIa) versus the (S) antipode (Formula VIb) or the (S) antipode(Formula VIb) versus the (R) antipode (Formula VIa), respectively. Aswill be described in the proceeding schemes, the penultimateintermediate of Formula VIa and VIb will allow for the generation ofcompounds of Formula Ia or Ib via the routes to be described.

As illustrated in Scheme A and Scheme P, a substituted phenyl reagent ofFormula II, wherein the composition of A is as described under FormulaIa & Ib, with the requirement that at least one of the substituents (X)attached to the reagent of Formula II is a nitrile group or a halogengroup, such as bromine, can be combined with a reagent of Formula III,wherein the composition of B is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula III is a halide group, such as bromine, or anitrile group, followed by treatment with a base, such as nBuLi,followed by treatment with aqueous acid, such as 1N HCl, to form abenzophenone intermediate of Formula XXI. Alternatively, a substitutedphenyl reagent of Formula II, wherein the composition of A is asdescribed under Formula Ia & Ib, with the requirement that at least oneof the substituents (X) attached to the reagent of Formula II is analdehyde group or a halogen group, such as bromine, can be combined witha reagent of Formula III, wherein the composition of B is as describedunder Formula Ia & Ib, with the requirement that at least one of thesubstituents (X) attached to the reagent of Formula III is a halidegroup, such as bromine, or an aldehyde group, followed by treatment witha base, such as nBuLi, followed by treatment with aqueous acid, such as1N HCl, to form a benzophenone intermediate of Formula XXI. Alternately,as illustrated in Scheme C and Scheme P, a substituted phenyl reagent ofFormula II, wherein the composition of A is as described under FormulaIa & Ib, with the requirement that at least one of the substituents (X)attached to the reagent of Formula II is an alkyl ester group, such as amethyl or an ethyl ester, can be combined with a reagent of Formula III,wherein the composition of B is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula III is a halide group, such as bromine, followedby treatment with a base, such as nBuLi, followed by treatment withaqueous acid, to yield a benzophenone intermediate of Formula XXI. Inaddition, as illustrated in Scheme C and Scheme P, a substituted phenylreagent of Formula II, wherein the composition of A is as describedunder Formula Ia & Ib, with the requirement that at least one of thesubstituents (X) attached to the reagent of Formula II is a halidegroup, such as bromine, can be combined with a reagent of Formula III,wherein the composition of B is as described under Formula Ia & Ib, withthe requirement that at least one of the substituents (X) attached tothe reagent of Formula III is an alkyl ester group, such as a methyl oran ethyl ester, followed by treatment with a base, such as nBuLi,followed by treatment with aqueous acid, to yield a benzophenoneintermediate of Formula XXI. As illustrated in Scheme O and Scheme P, asubstituted phenyl reagent of Formula XIX, wherein the composition of Ais as described under Formula Ia & Ib, with the requirement that atleast one of the substituents attached to the reagent of Formula XIX isa N-methoxy-N-methylacetamide group, can be combined with a reagent ofFormula III, wherein the composition of B is as described under FormulaIa & Ib, with the requirement that at least one of the substituents (X)attached to the reagent of Formula III is a halide group, followed bytreatment with a base, such as nBuLi, followed by treatment with aqueousacid, to yield a benzophenone intermediate of Formula XXI, or asubstituted phenyl reagent of Formula II, wherein the composition of Ais as described under Formula Ia & Ib, with the requirement that atleast one of the substituents attached to the reagent of Formula II is ahalide group, such as bromine, can be combined with a reagent of FormulaXX, wherein the composition of B is as described under Formula Ia & Ib,with the requirement that at least one of the substituents (X) attachedto the reagent of Formula XX, is a N-methoxy-N-methylacetamide group,followed by treatment with a base, such as nBuLi, followed by treatmentwith aqueous acid, to yield a benzophenone intermediate of Formula XXI.Numerous alternate approaches well known to one skilled in the art canalso be employed to generate a benzophenone intermediate of Formula XXI.

As illustrated in Scheme P, an intermediate benzophenone of Formula XXIcan be treated with an agent such as1-(isocyanomethylsulfonyl)-4-methylbenzene (TosMIC) and a base, such aspotassium tert-butoxide, to yield an intermediate of Formula XXII.Hydrolysis of an intermediate of Formula XXII can be accomplished bytreatment with an acid, such as aqueous H₂SO₄ and acetic acid, to yieldan intermediate of Formula XXIII. An intermediate of Formula XXIII canbe treated with a base, such as n-butyl lithium, followed by an alkylhalide reagent of Formula XXIV, where X is a halide, such as chlorine,bromine or iodine and the composition of C is as described under FormulaIa and Ib, to yield an intermediate of Formula XXVa and XXVb, which arekey intermediates for the synthesis of compounds of Formula Ia and Ib.

As illustrated in Scheme Q, an intermediate of Formula XXVa/b can betreated with an agent such as diphenylphosphoryl azide (DPPA) in thepresence of a base, such as triethyl amine (TEA), followed by treatmentwith an agent, such as 2-(trimethylsilyl)ethanol or tert-butyl alcoholand eventual cleavage of the resulting intermediate carbamate bytreatment with agents such as tetrabutylammonium fluoride (TBAF) ortrifluoroacetic acid, to yield the advanced intermediate of FormulaVIa/b, which is a key intermediate for the synthesis of compounds ofFormula Ia and Ib. An intermediate of Formula XXVa/b can be treated withan agent such as diphenylphosphoryl azide (DPPA) in the presence of abase, such as triethyl amine (TEA), followed by treatment with an agentof formula R₃NH₂, were R₃ is defined as described under Formula Ia andIb, to give compounds of Formula X, which are compounds of Formula Iaand Ib. In addition, an intermediate of Formula XXVa/b can be treatedwith an agent such as diphenylphosphoryl azide (DPPA) in the presence ofa base, such as triethyl amine (TEA), followed by treatment with anagent of formula R₄OH, were R₄ is defined as described under Formula Iaand Ib, to give compounds of Formula XI, which are compounds of FormulaIa and Ib.

As illustrated in Scheme R, an intermediate of Formula XXI, made asdescribed in Schemes P, can be treated with a reagent such as NH₂OH, inthe presence of an acid such as HCl, followed by treatment with a basesuch as pyridine, to yield an intermediate of Formula XXVI. Anintermediate of Formula XXVI can be treated with a reducing agent suchas zinc, along with NH₄OAc and NH₄OH, to yield an intermediate ofFormula XXVII. An intermediate of Formula XXVII can be treated with aformylating agent, such as acetic formic anhydride, followed bydehydration through treatment with an agent such as POCl₃, to yield theisonitrile intermediate of Formula XXVIII. The isonitrile intermediateof Formula XXVIII can be treated with a base, such as aqueous KOH, alongwith tetrabutylammonium bromide, followed by an alkyl halide reagent ofFormula XXIV where the composition of C is as described under Formula Iaand Ib, and the X can be a halide, such as chlorine, bromine or iodine,to yield intermediates of Formula XXIXa and XXIXb, which are keyintermediates for the synthesis of compounds of Formula Ia and Ib. Theformation of an intermediate of Formula XXIXa or XXIXb from anintermediate of Formula XXVIII, as described above, can also beperformed in the presence of a chiral catalyst such as, but not limitedto, N-benzylcinchoninium chloride or N-benzylcinchonidinium chloride, toenrich the formation of the intermediate of Formula XXIXa over theintermediate of Formula XXIXb or to enrich the formation of theintermediate of Formula XXIXb over the intermediate of Formula XXIXa asneeded to make compounds of Formula Ia and Ib.

As illustrated in Scheme S, an intermediate of Formula XXIXa/b can beconverted to an intermediate of Formula VIa/b by treatment with an acidsuch as HCl in methanol. As described in earlier schemes, andintermediate of Formula VIa/b is a key intermediate for the synthesis ofcompounds of Formula Ia and Ib. In addition, an intermediate of FormulaXXIXa/b can be treated directly with an aldehyde of Formula R₃CHO, wherethe definition of R₃ is as described under Formula Ia and Ib, and anacid, such as trifluoroacetic acid, in the presence of a base, such aspyridine, to yield compounds of Formula XXXa/b, which are a compounds ofFormula Ia and Ib.

As illustrated in Scheme T, an intermediate of Formula XXI, made asdescribed in Schemes P, can be reacted with a reagent of Formula XXXI,where the composition of C is as described under Formula Ia and Ib, toyield a styrene intermediate of Formula XXXII. A reagent of FormulaXXXII can be derived from a variety of commercially availableintermediates or can readily be made by one skilled in the art. Astyrene intermediate of Formula XXXII can be treated with anexpoxidizing agent, such assodium chlorite in the presence of4-phenylpyridine-N-oxide, with or without a chiral catalyst such as,(1R,2R)-(−)-[1,2-cyclo-hexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene)]manganese(III) chloride, (R,R-MnCl (salen)), to obtain an oxirane intermediate ofFormula XXXIII. Treatment of the oxirane intermediate of Formula XXXIIIwith an agent such as NaN₃, in the presence of a Lewis acid such asethylaluminum dichloride, yields the azide intermediate of FormulaXXXIV. Reduction of the azide intermediate of Formula XXXIV can beachieved over palladium on charcoal in the presence of H₂ gas togenerate the advanced intermediate of Formula XXXIV. An intermediate ofFormula XXXV is embodied by the intermediate of Formula VIa/b which is akey intermediate on route to the synthesis of compounds of Formula Iaand Ib.

As illustrated in Scheme U, an intermediate of Formula VIa/b, can beconverted to an intermediate of compound XXXIIIa/b by treatment with aformylating agent, such as, acetic formic anhydride, followed by adehydrating agent, such as phosphorous oxychloride, along with a base,such as triethylamine. As described in Scheme S, an intermediate ofFormula XXIXa/b can be utilized to make compounds of Formula Ia and Ib.

As illustrated in Scheme V, an intermediate of Formula XXIXa/b, can betreated with an aldehyde reagent of Formula R₃CHO, where R₃ is asdescribed for Formula Ia and Ib, along with an acid, such as formicacid, and an amine reagent, of general formula X—NH₂, where X representsa cleavable protection group selected readily by one skilled in the art,followed by treatment with and acid, such as HCl, in the presence of analcohol and water, to yield a compound of Formula XXXVI, which is acompound of Formula Ia and Ib. Alternately a reagent of Formula XXIXa/bcan be treated with an anhydride reagent of Formula (R₃CO)₂O, where R₃is as described for Formula Ia and Ib, to yield a compound of FormulaXXXVII, which is a compound of Formula Ia and Ib.

As illustrated in Scheme W, by applications of routes described inSchemes A, B, C and O for the synthesis of an intermediate of FormulaVII, one skilled in the art can make intermediates of Formula XXXVII andXXXX, where the definition of A, B and C are as defined for Formula Iaand Ib. An intermediate of Formula XXXVIII can be reacted with anintermediate of Formula XXXIX, where X is a halogen, such as bromine,iodine or chlorine, and the definition of C is as described for FormulaIa and Ib, in the presence of a base, such as n-butyl lithium ortert-butyl lithium, along with a metalating agent such as, CH₃Al orMgBr₂, followed by hydrolysis of the sulfinamide, to yield theintermediate of Formula VIa and VIb, which is a key intermediate onroute to compounds of Formula Ia and Ib. An intermediate of Formula XXXXcan be reacted with an intermediate of Formula XXXXI, where X is ahalogen, such as bromine, iodine or chlorine, and the definition of A isas described for Formula Ia and Ib, in the presence of a base, such asn-butyl lithium or tert-butyl lithium, along with a metalating agentsuch as, CH₃Al, followed by hydrolysis of the sulfinamide, to yield theintermediate of Formula VIa and VIb, which is a key intermediate onroute to compounds of Formula Ia and Ib.

The above schemes give an overview of several general processes for thesynthesis of compounds of Formula Ia and Ib. Additional compounds ofFormula Ia and Ib can readily be made by one of ordinary skill in theart by further modification of functional groups at positions A, B, C orR₁ of compounds of Formula Ia and Ib made by the processes illustratedin the included schemes. The Examples that follow described numerousapplications of the routes described in Schemes A-W as well asadditional routes to compounds of Formula Ia and Ib achieved throughmodification of functional groups at positions A, B, C or R₁ ofcompounds of Formula Ia and Ib.

Utility

Compounds of the present invention have been shown to inhibitcholesterol ester transfer protein (CETP) by greater than 30% at twodifferent concentrations of less than 100 uM, preferably with a potencyless than 5 uM, more preferably with a potency less than 500 nM.Compounds of the invention were also found to inhibit cholesterol estertransfer activity using in vitro assays that contained up to 96% plasma,and to inhibit plasma cholesterol ester transfer activity in animals.Accordingly, compounds within the scope of the present invention inhibitthe CETP protein, and as such are expected to be useful in thetreatment, prevention, and/or slowing of the progression of variousdisorders.

For example, the compounds of the present invention, their prodrugs andthe salts of such compounds and prodrugs can be adapted to therapeuticuse as agents that inhibit cholesterol ester transfer protein activityin mammals, particularly humans. Thus, the compounds of the presentinvention are expected to be useful in elevating plasma HDL cholesterol,its associated components, and the functions performed by them inmammals, particularly humans. By virtue of their expected activity,these agents are also expected to reduce VLDL cholesterol, LDLcholesterol and their associated components in mammals, particularlyhumans. Hence, these compounds are expected to be useful for thetreatment and correction of the various dyslipidemias observed to beassociated with the development and incidence of atherosclerosis andcardiovascular disease, including hypoalphalipoproteinemia,hyperbetalipoproteinemia, hypertriglyceridemia, andfamilial-hypercholesterolemia (see U.S. Pat. No. 6,489,478, incorporatedherein by reference).

Further, introduction of a functional CETP gene into an animal lackingCETP (mouse) results in reduced HDL levels (Agellon, L. B. et al., J.Biol. Chem., 266:10796-10801 (1991)) and, increased susceptibility toatherosclerosis. (Marotti, K. R. et al., Nature, 364:73-75 (1993)).Also, inhibition of CETP activity with an inhibitory antibody raisesHDL-cholesterol in hamster (Evans, G. F. et al., J. Lipid Research,35:1634-1645 (1994)) and rabbit (Whitlock, M. E. et al, J. Clin.Invest., 84:129-137 (1989)). Suppression of increased plasma CETP byintravenous injection with antisense oligodeoxynucleotides against CETPmRNA reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M. etal., J. Biol. Chem., 273:5033-5036 (1998)). Importantly, human subjectsdeficient in plasma CETP, due to a genetic mutation possess markedlyelevated plasma HDL-cholesterol levels and apolipoprotein A-I, the majorapoprotein component of HDL. In addition, most demonstrate markedlydecreased plasma LDL cholesterol and apolipoprotein B (the majorapolipoprotein component of LDL. (Inazu, A. et al., N. Engl. J. Med.,323:1234-1238 (1990)).

Given the negative correlation between the levels of HDL cholesterol andHDL associated lipoproteins, and the positive correlation betweentriglycerides, LDL cholesterol, and their associated apolipoproteins inblood with the development of cardiovascular, cerebral vascular andperipheral vascular diseases, the compounds of the present invention,their prodrugs and the salts of such compounds and prodrugs, by virtueof their pharmacologic action, are expected to be useful for thetreatment, prevention, the arrestment and/or regression ofatherosclerosis and its associated disease states. These includecardiovascular disorders (e.g., angina, cardiac ischemia and myocardialinfarction), complications due to cardiovascular disease therapies(e.g., reperfusion injury and angioplastic restenosis), hypertension,stroke, and atherosclerosis associated with organ transplantation.

Because of the beneficial effects widely associated with elevated HDLlevels, an agent which inhibits CETP activity in humans, by virtue ofits HDL increasing ability, also provides valuable avenues for therapyin a number of other disease areas as well.

Accordingly, given the ability of the compounds of the presentinvention, their prodrugs and the salts of such compounds and prodrugsto alter lipoprotein composition via inhibition of cholesterol estertransfer, they are expected to be useful in the treatment, preventionand/or slowing of the progression of vascular complications associatedwith diabetes. Hyperlipidemia is present in most subjects with diabetesmellitus (Howard, B. V., J. Lipid Res. 28:613 (1987)). Even in thepresence of normal lipid levels, diabetic subjects experience a greaterrisk of cardiovascular disease (Kannel, W. B. et al., Diabetes Care,2:120 (1979)). CETP-mediated cholesteryl ester transfer is known to beabnormally increased in both insulin-dependent (Bagdade, J. D. et al.,Eur. J. Clin. Invest., 21:161 (1991)) and non-insulin dependent diabetes(Bagdade, J. D. et al., Atherosclerosis, 104:69 (1993)). It has beensuggested that the abnormal increase in cholesterol transfer results inchanges in lipoprotein composition, particularly for VLDL and LDL, thatare more atherogenic (Bagdade, J. D. et al., J. Lipid Res., 36:759(1995)). These changes would not necessarily be observed during routinelipid screening. Thus, it is expected that the present invention will beuseful in reducing the risk of vascular complications as a result of thediabetic condition.

In addition, the compounds of the present invention are expected to beuseful in the treatment of obesity. In both humans (Radeau, T. et al.,J. Lipid Res., 36(12):2552-2561 (1995)) and nonhuman primates (Quinet,E. et al., J. Clin. Invest., 87(5):1559-1566 (1991)) mRNA for CETP isexpressed at high levels in adipose tissue. The adipose messageincreases with fat feeding (Martin, L. J. et al., J. Lipid Res.,34(3):437-446 (1993)), and is translated into functional transferprotein and through secretion contributes significantly to plasma CETPlevels. In human adipocytes the bulk of cholesterol is provided byplasma LDL and HDL (Fong, B. S. et al., Biochimica et Biophysica Acta,1004(1):53-60 (1989)). The uptake of HDL cholesteryl ester is dependentin large part on CETP (Benoist, F. et al., J. Biol. Chem.,272(38):23572-23577 (1997)). This ability of CETP to stimulate HDLcholesteryl uptake, coupled with the enhanced binding of HDL toadipocytes in obese subjects (Jimenez, J. G. et al., Int. J. Obesity,13(5):699-709 (1989)), suggests a role for CETP, not only in generatingthe low HDL phenotype for these subjects, but in the development ofobesity itself by promoting cholesterol accumulation. Inhibitors of CETPactivity that block this process therefore serve as useful adjuvants todietary therapy in causing weight reduction.

CETP inhibitors are useful in the treatment of inflammation due toGram-negative sepsis and septic shock. For example, the systemictoxicity of Gram-negative sepsis is in large part due to endotoxin, alipopolysaccharide (LPS) released from the outer surface of thebacteria, which causes an extensive inflammatory response.Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R. J.et al., J. Clin. Invest. 67:827-837 (1981)). In vitro studies havedemonstrated that binding of LPS to HDL substantially reduces theproduction and release of mediators of inflammation (Ulevitch, R. J. etal., J. Clin. Invest. 62:1313-1324 (1978)). In vivo studies show thattransgenic mice expressing human apo-Al and elevated HDL levels areprotected from septic shock (Levine, D. M. et al., Proc. Natl. Acad.Sci., 90:12040-12044 (1993)). Importantly, administration ofreconstituted HDL to humans challenged with endotoxin resulted in adecreased inflammatory response (Pajkrt, D. et al., J. Exp. Med.,184:1601-1608 (1996)). The CETP inhibitors, by virtue of the fact thatthey raise HDL levels, attenuate the development of inflammation andseptic shock.

Thus, the present invention provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the present invention, its prodrug and thesalt of such compound and prodrugs. Other therapeutic agents such asthose described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

In addition, the compounds of the present invention are expected to beuseful in the inhibition of remnant lipoprotein production (Okamoto etal., WO 2005/030185).

CETP Assay

CETP inhibition can be determined at a specific concentration of testcompound in any of the assays described herein. Potencies are moregenerally calculated by determining IC₅₀ values using these assays.

CETP Scintillation Proximity Assay

Compounds of the present invention inhibit CETP-dependent cholesterolester transfer from HDL to LDL as described here. Dilutions of compoundsin DMSO (1 μl) are added to BD plates (#353232). To this is added 20 μlof a mixture containing ³H-CE/HDL (0.15 μl), biotinylated LDL (˜5 μgprotein/ml final concentration) and unlabeled HDL (16 μg/ml finalconcentration) in a buffer containing 50 mM HEPES, pH 7.4, 150 mM NaCland 0.05% sodium azide. Reactions are initiated by the addition of 10 μlof buffer containing purified human recombinant CETP, and incubated at37° C. At the end of the reaction, 60 μl of LEADseeker beads (#RPNQ0261,2 mg/ml in buffer containing 1 mg/ml BSA and 0.05 mg protein/ml HDL) areadded, the plates are covered and subsequently read. Background activityis determined in a set of wells that receive buffer but no CETP. Thelevel of inhibition is determined by comparing the readings in wellsthat contain compound to the readings in control wells containing DMSO.

Plasma Cholesterol Ester Transfer Assay

Compounds of the present invention were also tested for the ability toinhibit cholesterol ester transfer activity in plasma as described here.Dilutions of compounds in DMSO (1 μl) are added to 384-wellpolypropylene plates. To each well is added 29 ul of human plasmacontaining 0.15 ul ³H-CE/HDL. The reaction is incubated at 37° C. andterminated by the addition of 6 ul of precipitation reagent (2:1:1 ofwater:1M MgCl₂:2% Dextralip 50), to precipitate LDL and VLDL. After 10minutes at room temperature, 15 μl of the reaction is transferred tofilter plates (Millipore, #MHVBN45) pre-wetted with 100 ul phosphatebuffered saline. The plates are centrifuged (1800 rpm) at roomtemperature for 10 minutes, and 50 ul Microscint-20 is added. The platesare then sealed and read. Background activity is determined with plasmasamples incubated at 4° C. The level of inhibition is determined bycomparing the readings in wells that contain compound to the readings incontrol wells containing DMSO.

In Vivo Cholesterol Ester Transfer Activity

Compounds of the present invention have further been shown to inhibitplasma cholesterol ester transfer activity in mice that are duallytransgenic for human CETP and apoB-100 (hCETP/apoB-100) as describedhere.

Mice (commercially available from Taconic) are fasted for two hours andplasma obtained before dosing. The animals are then dosed with vehicleor compound (p.o.). The vehicle may vary as needed to dissolve thecompound, while at the same time having no, or minimal, activity onplasma cholesterol ester transfer activity. Plasma samples are collectedagain at various times after dosing and assayed for cholesterol estertransfer activity.

To measure CETP activity in plasma samples obtained from animals treatedwith compounds, the following methodology is employed. To a sample ofplasma (typically between 9 and 30 ul), 1 μl of diluted ³H-CE/HDL isadded (0.15 μl ³H-CE/HDL and 0.85 ul assay buffer) to label endogenousHDL. Assay buffer contains 50 mM HEPES, pH 7.4, and 150 mM NaCl. Thereaction is incubated at 37° C., and LDL/VLDL precipitated with 3 μl ofprecipitation reagent (4:1:1 of water:0.5M MgCl₂:1% Dextralip 50). Thetubes are centrifuged for 15-30 minutes at 10,000×g (10° C.), thesupernatants discarded, and the pellets dissolved in 140 μl of 2% SDS.Half of the SDS solution (70 μl) is transferred to scintillation tubes,scintillation fluid is added, and radioactivity measured in ascintillation counter. Background activity is determined for each samplewith an aliquot incubated at 4° C. Plasma cholesterol ester transferinhibition is calculated by comparing the transfer activity in a plasmasample obtained after dosing to the transfer activity in the plasmasample obtained from the same animal before dosing. All data arebackground subtracted.

The in vivo assay described above (with appropriate modifications withinthe skill in the art) may be used to determine the activity of otherlipid or triglyceride controlling agents as well as the compounds ofthis invention. The assays set forth above also provide a means wherebythe activities of the compounds of the present invention, their prodrugsand the salts of such compounds and prodrugs (or the other agentsdescribed herein) can be compared to each other and with the activitiesof other known compounds. The results of these comparisons are usefulfor determining dosage levels in mammals, including humans, for thetreatment of the above described disease/conditions.

HDL Cholesterol Protocol

The ability of CETP inhibitors to increase HDL cholesterol (HDL-C) canbe shown in mammalian subjects via methods known to one of ordinaryskill in the art (see Evans, G. F. et al., J. Lipid Research,35:1634-1645 (1994)). For example, compounds of the present inventionhave been shown to be efficacious in the elevation of HDL-C in goldensyrian hamsters. The hamsters are fed a moderate fat diet containingvariable amounts of coconut oil and cholesterol to alter their HDL-C andLDL-C levels. The moderately fat-fed hamsters are fasted and bled todetermine baseline HDL-C levels, then dosed orally with compound forthree days in an appropriate vehicle. The animals are fasted and bledagain on the third day of dosing, and the results are compared to thebaseline HDL-C levels. The compounds increase HDL-C in this model in adose-dependent manner, demonstrating their usefulness to alter plasmalipids.

Antiobesity Protocol

The ability of CETP inhibitors to cause weight loss can be assessed inobese human subjects with body mass index (BMI) ≧30 kg/m². Doses ofinhibitor are administered sufficient to result in an increase of ≧25%in HDL cholesterol levels. BMI and body fat distribution, defined aswaist (W) to hip (H) ratio (WHR), are monitored during the course of the3-6 month studies, and the results for treatment groups compared tothose receiving placebo.

The above assays can of course be varied by those skilled in the art.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the present invention, theirprodrugs and the salts of such compounds and prodrugs capable ofpreventing, treating, and/or slowing the progression of one or more ofthe aforementioned disorders in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may contain other therapeutic agents as describedbelow, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the present invention may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; bucally; parenterally, suchas by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds may, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release may be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of present invention may also be deliveredthrough the oral cavity by sublingual and/or buccal administration.Molded tablets, compressed tablets or freeze-dried tablets are exemplaryforms which may be used. Exemplary compositions include thoseformulating the present compound(s) with fast dissolving diluents suchas mannitol, lactose, sucrose and/or cyclodextrins. Also included insuch formulations may be high molecular weight excipients such ascelluloses (avicel) or polyethylene glycols (PEG). Such formulations mayalso include an excipient to aid mucosal adhesion such as hydroxy propylcellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), andagents to control release such as polyacrylic copolymer (e.g., Carbopol934). Lubricants, glidants, flavors, coloring agents and stabilizers mayalso be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitable nontoxic, parenterally acceptable diluents or solvents, such as mannitol,1,3 butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders.

For example, they may be used in combination with a HMG-CoA reductaseinhibitor, a cholesterol synthesis inhibitor, a cholesterol absorptioninhibitor, another CETP inhibitor, a MTP/Apo B secretion inhibitor, aPPAR modulator and other cholesterol lowering agents such as a fibrate,niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, and abile acid sequestrant. Other pharmaceutical agents would also includethe following: a bile acid reuptake inhibitor, an ileal bile acidtransporter inhibitor, an ACC inhibitor, an antihypertensive (such asNORVASC®), a selective estrogen receptor modulator, a selective androgenreceptor modulator, an antibiotic, an antidiabetic (such as metformin, aPPARγ activator, a sulfonylurea, insulin, an aldose reductase inhibitor(ARI) and a sorbitol dehydrogenase inhibitor (SDI)), aspirin(acetylsalicylic acid) and niacin and combinations thereof.

Any HMG-CoA reductase inhibitor may be used in the combination aspect ofthis invention. The term HMG-CoA reductase inhibitor refers to compoundswhich inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A tomevalonic acid catalyzed by the enzyme HMG-CoA reductase. Suchinhibition is readily determined by those skilled in the art accordingto standard assays (e.g., Meth. Enzymol., 71:455-509 (1981) andreferences cited therein). A variety of these compounds are describedand referenced below however other HMG-CoA reductase inhibitors will beknown to those skilled in the art. U.S. Pat. No. 4,231,938 (thedisclosure of which is hereby incorporated by reference) disclosescertain compounds isolated after cultivation of a microorganismbelonging to the genus Aspergillus, such as Iovastatin. Also, U.S. Pat.No. 4,444,784 (the disclosure of which is hereby incorporated byreference) discloses synthetic derivatives of the aforementionedcompounds, such as simvastatin. Also, U.S. Pat. No. 4,739,073 (thedisclosure of which is incorporated by reference) discloses certainsubstituted indoles, such as fluvastatin. Also, U.S. Pat. No. 4,346,227(the disclosure of which is incorporated by reference) discloses ML-236Bderivatives, such as pravastatin. Also, EP-491226A (the disclosure ofwhich is incorporated by reference) discloses certainpyridyldihydroxyheptenoic acids, such as cerivastatin. In addition, U.S.Pat. No. 5,273,995 (the disclosure of which is incorporated byreference) discloses certain6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatinand any pharmaceutically acceptable form thereof (i.e. LIPITOR®).Additional HMG-CoA reductase inhibitors include rosuvastatin andpitavastatin. Statins also include such compounds as rosuvastatindisclosed in U.S. RE37,314 E, pitavastatin disclosed in EP 304063 B1 andU.S. Pat. No. 5,011,930; mevastatin, disclosed in U.S. Pat. No.3,983,140; velostatin, disclosed in U.S. Pat. No. 4,448,784 and U.S.Pat. No. 4,450,171; compactin, disclosed in U.S. Pat. No. 4,804,770;dalvastatin, disclosed in European Patent Application Publication No.738510 A2; fluindostatin, disclosed in European Patent ApplicationPublication No. 363934 A1; and dihydrocompactin, disclosed in U.S. Pat.No. 4,450,171.

Any PPAR modulator may be used in the combination aspect of thisinvention. The term PPAR modulator refers to compounds which modulateperoxisome proliferator activator receptor (PPAR) activity in mammals,particularly humans. Such modulation is readily determined by thoseskilled in the art according to standard assays known in the literature.It is believed that such compounds, by modulating the PPAR receptor,regulate transcription of key genes involved in lipid and glucosemetabolism such as those in fatty acid oxidation and also those involvedin high density lipoprotein (HDL) assembly (for example, apolipoproteinAI gene transcription), accordingly reducing whole body fat andincreasing HDL cholesterol. By virtue of their activity, these compoundsalso reduce plasma levels of triglycerides, VLDL cholesterol, LDLcholesterol and their associated components such as apolipoprotein B inmammals, particularly humans, as welt as increasing HDL cholesterol andapolipoprotein AI. Hence, these compounds are useful for the treatmentand correction of the various dyslipidemias observed to be associatedwith the development and incidence of atherosclerosis and cardiovasculardisease, including hypoalphalipoproteinemia and hypertriglyceridemia. Avariety of these compounds are described and referenced below, however,others will be known to those skilled in the art. InternationalPublication Nos. WO 02/064549 and WO 02/064130, U.S. patent applicationSer. No. 10/720,942, and U.S. patent application 60/552,114 disclosecertain compounds which are PPARα activators.

Any other PPAR modulator may be used in the combination aspect of thisinvention. In particular, modulators of PPARβ and/or PPARγ may be usefulin combination with compounds of the present invention. An example PPARinhibitor is described in US 2003/0225158 as{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzy]oxy)-benzylsulfany]-phenoxy}-aceticacid.

Any MTP/Apo B (microsomal triglyceride transfer protein and orapolipoprotein B) secretion inhibitor may be used in the combinationaspect of this invention. The term MTP/Apo B secretion inhibitor refersto compounds which inhibit the secretion of triglycerides, cholesterylester, and phospholipids. Such inhibition is readily determined by thoseskilled in the art according to standard assays (e.g., Wetterau, J. R.,Science, 258:999 (1992)). A variety of these compounds are described andreferenced below however other MTP/Apo B secretion inhibitors will beknown to those skilled in the art, including implitapride (Bayer) andadditional compounds such as those disclosed in WO 96/40640 and WO98/23593, (two exemplary publications). For example, the followingMTP/Apo B secretion inhibitors are particularly useful:4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(1H-[1,2,4,]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2-acetylamino-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-carbamicacid methyl ester; 4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2,2-diphenyl-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2-ethoxy-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-2-carboxamide;(S)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylicacid (pentylcarbamoyl-phenyl-methyl)-amide; 1H-indole-2-carboxamide,1-methyl-N-[(1S)-2-[methyl(phenylmethyl)amino]-2-oxo-1-phenylethyl]-5-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino];andN-[(1S)-2-(benzylmethylamino)-2-oxo-1-phenylethyl]-1-methyl-5-[[[4′-(thfluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1H-indole-2-carboxamide.

Any HMG-CoA synthase inhibitor may be used in the combination aspect ofthis invention. The term HMG-CoA synthase inhibitor refers to compoundswhich inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A fromacetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzymeHMG-CoA synthase. Such inhibition is readily determined by those skilledin the art according to standard assays (Meth. Enzymol., 35:155-160(1975); Meth. Enzymol., 110:19-26 (1985) and references cited therein).A variety of these compounds are described and referenced below, howeverother HMG-CoA synthase inhibitors will be known to those skilled in theart. U.S. Pat. No. 5,120,729 discloses certain beta-lactam derivatives.U.S. Pat. No. 5,064,856 discloses certain spiro-lactone derivativesprepared by culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271discloses certain oxetane compounds such as11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoicacid derivatives.

Any compound that decreases HMG-CoA reductase gene expression may beused in the combination aspect of this invention. These agents may beHMG-CoA reductase transcription inhibitors that block the transcriptionof DNA or translation inhibitors that prevent or decrease translation ofmRNA coding for HMG-CoA reductase into protein. Such compounds mayeither affect transcription or translation directly, or may bebiotransformed to compounds that have the aforementioned activities byone or more enzymes in the cholesterol biosynthetic cascade or may leadto the accumulation of an isoprene metabolite that has theaforementioned activities. Such compounds may cause this effect bydecreasing levels of SREBP (sterol receptor binding protein) byinhibiting the activity of site-1 protease (SIP) or agonizing theoxysterol receptor or SCAP. Such regulation is readily determined bythose skilled in the art according to standard assays (Meth. Enzymol.,110:9-19 (1985)). Several compounds are described and referenced below,however other inhibitors of HMG-CoA reductase gene expression will beknown to those skilled in the art. U.S. Pat. No. 5,041,432 disclosescertain 15-substituted lanosterol derivatives. Other oxygenated sterolsthat suppress synthesis of HMG-CoA reductase are discussed by E. I.Mercer (Prog. Lip. Res., 32:357-416 (1993)).

Any compound having activity as a CETP inhibitor can serve as the secondcompound in the combination therapy aspect of the present invention. Theterm CETP inhibitor refers to compounds that inhibit the cholesterylester transfer protein (CETP) mediated transport of various cholesterylesters and triglycerides from HDL to LDL and VLDL. Such CETP inhibitionactivity is readily determined by those skilled in the art according tostandard assays (e.g., U.S. Pat. No. 6,140,343). A variety of CETPinhibitors will be known to those skilled in the art, for example, thosedisclosed in U.S. Pat. Nos. 6,140,343 and 6,197,786. CETP inhibitorsdisclosed in these patents include compounds, such as[2R,4S]-4-[(3,5-bis-trifluoromethylbenzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (torcetrapib). CETP inhibitors are also described inU.S. Pat. No. 6,723,752, which includes a number of CETP inhibitorsincluding(2R)-3-{[3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino}-1,1,1-trifluoro-2-propanol.Moreover, CETP inhibitors included herein are also described in U.S.patent application Ser. No. 10/807,838 and PCT Publication No. WO2006/090250. U.S. Pat. No. 5,512,548 discloses certain polypeptidederivatives having activity as CETP inhibitors, while certainCETP-inhibitory rosenonolactone derivatives and phosphate-containinganalogs of cholesteryl ester are disclosed in J. Antibiot.,49(8):815-816 (1996), and Bioorg. Med. Chem. Lett., 6:1951-1954 (1996),respectively.

Any squalene synthetase inhibitor may be used in the combination aspectof this invention. The term squalene synthetase inhibitor refers tocompounds which inhibit the condensation of 2 molecules offarnesylpyrophosphate to form squalene, catalyzed by the enzyme squalenesynthetase. Such inhibition is readily determined by those skilled inthe art according to standard assays (Meth. Enzymol., 15:393-454 (1969)and Meth. Enzymol., 110:359-373 (1985) and references containedtherein). A variety of these compounds are described in and referencedbelow however other squalene synthetase inhibitors will be known tothose skilled in the art. U.S. Pat. No. 5,026,554 discloses fermentationproducts of the microorganism MF5465 (ATCC 74011) including zaragozicacid. A summary of other patented squalene synthetase inhibitors hasbeen compiled (Curr. Op. Ther. Patents, 861-864 (1993)).

Any squalene epoxidase inhibitor may be used in the combination aspectof this invention. The term squalene epoxidase inhibitor refers tocompounds which inhibit the bioconversion of squalene and molecularoxygen into squalene-2,3-epoxide, catalyzed by the enzyme squaleneepoxidase. Such inhibition is readily determined by those skilled in theart according to standard assays (Biochim. Biophys. Acta, 794:466-471(1984)). A variety of these compounds are described and referencedbelow, however other squalene epoxidase inhibitors will be known tothose skilled in the art. U.S. Pat. Nos. 5,011,859 and 5,064,864disclose certain fluoro analogs of squalene. EP publication 395,768 Adiscloses certain substituted allylamine derivatives. PCT publication WO93/12069 A discloses certain amino alcohol derivatives. U.S. Pat. No.5,051,534 discloses certain cyclopropyloxy-squalene derivatives.

Any squalene cyclase inhibitor may be used as the second component inthe combination aspect of this invention. The term squalene cyclaseinhibiter refers to compounds which inhibit the bioconversion ofsqualene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalenecyclase. Such inhibition is readily determined by those skilled in theart according to standard assays (FEBS Lett., 244:347-350 (1989)). Inaddition, the compounds described and referenced below are squalenecyclase inhibitors, however other squalene cyclase inhibitors will alsobe known to those skilled in the art. PCT publication WO 94/10150discloses certain1,2,3,5,6,7,8,8a-octahydro-5,5,8(beta)-trimethyl-6-isoquinolineaminederivatives, such asN-trifluoroacetyl-1,2,3,5,6,7,8,8a-octahydro-2-allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine.French patent publication 2697250 discloses certain beta,beta-dimethyl-4-piperidine ethanol derivatives such as1-(1,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethanol.

Any combined squalene epoxidase/squalene cyclase inhibitor may be usedas the second component in the combination aspect of this invention. Theterm combined squalene epoxidase/squalene cyclase inhibitor refers tocompounds that inhibit the bioconversion of squalene to lanosterol via asqualene-2,3-epoxide intermediate. In some assays it is not possible todistinguish between squalene epoxidase inhibitors and squalene cyclaseinhibitors, however, these assays are recognized by those skilled in theart. Thus, inhibition by combined squalene epoxidase/squalene cyclaseinhibitors is readily determined by those skilled in art according tothe aforementioned standard assays for squalene cyclase or squaleneepoxidase inhibitors. A variety of these compounds are described andreferenced below, however other squalene epoxidase/squalene cyclaseinhibitors will be known to those skilled in the art. U.S. Pat. Nos.5,084,461 and 5,278,171 disclose certain azadecalin derivatives. EPpublication 468,434 discloses certain piperidyl ether and thio-etherderivatives such as 2-(1-piperidyl)pentyl isopentyl sulfoxide and2-(1-piperidyl)ethyl ethyl sulfide. PCT publication WO 94/01404discloses certain acyl-piperidines such as1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine.U.S. Pat. No. 5,102,915 discloses certain cyclopropyloxy-squalenederivatives.

The compounds of the present invention may also be administered incombination with naturally occurring compounds that act to lower plasmaLDL cholesterol levels or raise plasma HDL levels via a pathway distinctfrom CETP inhibitors. These naturally occurring compounds are commonlycalled nutraceuticals and include, for example, garlic extract andniacin. Niacin is a particularly attractive secondary agent forcombination with a CETP inhibitor as it also raises HDL cholesterollevels. Furthermore, niacin lowers LDL cholesterol and triglycerides.Therefore, a combination of niacin and a CETP inhibitor would not onlyprovide the potential for enhanced HDL-raising efficacy, it would yielda very favorable shift in the overall cardiovascular risk profile bydecreasing LDL cholesterol and triglycerides. Niacin is commerciallyavailable in various dosage forms. Immediate release niacin may bepurchase over-the-counter in pharmacies or health-food stores. Aslow-release form of niacin is available and is known as Niaspan. Niacinmay also be combined with other therapeutic agents such as iovastatin,an HMG-CoA reductase inhibitor. This combination therapy with iovastatinis known as ADVICOR™ (Kos Pharmaceuticals Inc.). In long term clinicaltrials, niacin either as monotherapy or in combination with HMG-CoAreductase inhibitors has been shown to reduce cardiovascular events,cardiovascular deaths and all cause mortality.

Any cholesterol absorption inhibitor can be used as an additionalcomponent in the combination aspect of the present invention. The termcholesterol absorption inhibition refers to the ability of a compound toprevent cholesterol contained within the lumen of the intestine fromentering into the intestinal cells and/or passing from within theintestinal cells into the lymph system and/or into the blood stream.Such cholesterol absorption inhibition activity is readily determined bythose skilled in the art according to standard assays (e.g., J. LipidRes., 34:377-395 (1993)). Cholesterol absorption inhibitors are known tothose skilled in the art and are described, for example, in PCT WO94/00480. An example of a recently approved cholesterol absorptioninhibitor is ZETIA™ (ezetimibe) (Schering-Plough/Merck).

Any ACAT inhibitor may be used in the combination therapy aspect of thepresent invention. The term ACAT inhibitor refers to compounds thatinhibit the intracellular esterification of dietary cholesterol by theenzyme acyl CoA: cholesterol acyltransferase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays, such as the method of Heider et al. described in J. Lipid Res.,24:1127 (1983). A variety of these compounds are known to those skilledin the art, for example, U.S. Pat. No. 5,510,379 discloses certaincarboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose ureaderivatives having ACAT inhibitory activity. Examples of ACAT inhibitorsinclude compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) andEflucimibe (Ell Lilly and Pierre Fabre).

A lipase inhibitor may be used in the combination therapy aspect of thepresent invention. A lipase inhibitor is a compound that inhibits themetabolic cleavage of dietary triglycerides or plasma phospholipids intofree fatty acids and the corresponding glycerides (e.g. EL, HL, etc.).Under normal physiological conditions, lipolysis occurs via a two-stepprocess that involves acylation of an activated serine moiety of thelipase enzyme. This leads to the production of a fatty acid-lipasehemiacetal intermediate, which is then cleaved to release a diglyceride.Following further deacylation, the lipase-fatty acid intermediate iscleaved, resulting in free lipase, a glyceride and fatty acid. In theintestine, the resultant free fatty acids and monoglycerides areincorporated into bile acid-phospholipid micelles, which aresubsequently absorbed at the level of the brush border of the smallintestine. The micelles eventually enter the peripheral circulation aschylomicrons. Such lipase inhibition activity is readily determined bythose skilled in the art according to standard assays (e.g., Meth.Enzymol. 286:190-231). Pancreatic lipase mediates the metabolic cleavageof fatty acids from triglycerides at the 1- and 3-carbon positions. Theprimary site of the metabolism of ingested fats is in the duodenum andproximal jejunum by pancreatic tipase, which is usually secreted in vastexcess of the amounts necessary for the breakdown of fats in the uppersmall intestine. Because pancreatic lipase is the primary enzymerequired for the absorption of dietary triglycerides, inhibitors haveutility in the treatment of obesity and the other related conditions.Such pancreatic lipase inhibition activity is readily determined bythose skilled in the art according to standard assays (e.g., Meth.Enzymol. 286:190-231).

Gastric lipase is an immunologically distinct lipase that is responsiblefor approximately 10 to 40% of the digestion of dietary fats. Gastriclipase is secreted in response to mechanical stimulation, ingestion offood, the presence of a fatty meal or by sympathetic agents. Gastriclipolysis of ingested fats is of physiological importance in theprovision of fatty acids needed to trigger pancreatic lipase activity inthe intestine and is also of importance for fat absorption in a varietyof physiological and pathological conditions associated with pancreaticinsufficiency. See, for example, Abrams, C. K. et al., Gastroenterology,92:125 (1987). Such gastric lipase inhibition activity is readilydetermined by those skilled in the art according to standard assays(e.g., Meth. Enzymol., 286:190-231).

A variety of gastric and/or pancreatic lipase inhibitors are known toone of ordinary skill in the art. Preferred lipase inhibitors are thoseinhibitors that are selected from the group consisting of lipstatin,tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A,and ebelactone B. The compound tetrahydrolipstatin is especiallypreferred. The lipase inhibitor,N-3-trifluoromethylphenyl-N′-3-chloro-4′-trifluoromethylphenylurea, andthe various urea derivatives related thereto, are disclosed in U.S. Pat.No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in U.S.Pat. Nos. 4,189,438 and 4,242,453. The lipase inhibitor,cyclo-O,O′-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and thevarious bis(iminocarbonyl)dioximes related thereto may be prepared asdescribed in Petersen et al., Liebig's Annalen, 562:205-229 (1949).

A variety of pancreatic lipase inhibitors are described herein below.The pancreatic lipase inhibitors lipstatin,(2S,3S,5S,7Z,10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoicacid lactone, and tetrahydrolipstatin (orlistat),(2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic1,3 acid lactone, and the variously substituted N-formylleucinederivatives and stereoisomers thereof, are disclosed In U.S. Pat. No.4,598,089. For example, tetrahydrolipstatin is prepared as described in,e.g., U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. Thepancreatic lipase inhibitor, FL-386,1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]ethanone, andthe variously substituted sulfonate derivatives related thereto, aredisclosed in U.S. Pat. No. 4,452,813. The pancreatic lipase inhibitor,WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and thevarious carbamate esters and pharmaceutically acceptable salts relatedthereto, are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and5,602,151. The pancreatic lipase inhibitor, valilactone, and a processfor the preparation thereof by the microbial cultivation ofActinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J.Antibiotics, 40(11):1647-1650 (1987). The pancreatic lipase inhibitors,ebelactone A and ebelactone B, and a process for the preparation thereofby the microbial cultivation of Actinomycetes strain MG7-G1, aredisclosed in Umezawa et al., J. Antibiotics, 33:1594-1596 (1980). Theuse of ebelactones A and B in the suppression of monoglyceride formationis disclosed in Japanese Kokai 08-143457, published Jun. 4, 1996.

Other compounds that are marketed for hyperlipidemia, includinghypercholesterolemia and which are intended to help prevent or treatatherosclerosis include bile acid sequestrants, such as Welchol®,Colestid®, LoCholest® and Questran®; and fibric acid derivatives, suchas Atromid®, Lopid® and Tricot®.

Diabetes can be treated by administering to a patient having diabetes(especially Type II), insulin resistance, impaired glucose tolerance,metabolic syndrome, or the like, or any of the diabetic complicationssuch as neuropathy, nephropathy, retinopathy or cataracts, atherapeutically effective amount of a compound of the present inventionin combination with other agents (e.g., insulin) that can be used totreat diabetes. This includes the classes of anti-diabetic agents (andspecific agents) described herein.

Any glycogen phosphorylase inhibitor can be used as the second agent incombination with a compound of the present invention. The term glycogenphosphorylase inhibitor refers to compounds that inhibit thebioconversion of glycogen to glucose-1-phosphate which is catalyzed bythe enzyme glycogen phosphorylase. Such glycogen phosphorylaseinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., J. Med. Chem. 41:2934-2938 (1998)).A variety of glycogen phosphorylase inhibitors are known to thoseskilled in the art including those described in WO 96/39384 and WO96/39385.

Any aldose reductase inhibitor can be used in combination with acompound of the present invention. The term aldose reductase inhibitorrefers to compounds that inhibit the bioconversion of glucose tosorbitol, which is catalyzed by the enzyme aldose reductase. Aldosereductase inhibition is readily determined by those skilled in the artaccording to standard assays (e.g., J. Malone, “Red Celt Sorbitol, anIndicator of Diabetic Control”, Diabetes, 29:861-864 (1980)). A varietyof aldose reductase inhibitors are known to those skilled in the art,such as those described in U.S. Pat. No. 6,579,879, which includes6-(5-chloro-3-methylbenzo furan-2-sulfonyl)-2H-pyridazin-3-one.

Any sorbitol dehydrogenase inhibitor can be used in combination with acompound of the present invention. The term sorbitol dehydrogenaseinhibitor refers to compounds that inhibit the bioconversion of sorbitolto fructose which is catalyzed by the enzyme sorbitol dehydrogenase.Such sorbitol dehydrogenase inhibitor activity is readily determined bythose skilled in the art according to standard assays (e.g., Analyt.Biochem., 280:329-331 (2000)). A variety of sorbitol dehydrogenaseinhibitors are known, for example, U.S. Pat. Nos. 5,728,704 and5,866,578 disclose compounds and a method for treating or preventingdiabetic complications by inhibiting the enzyme sorbitol dehydrogenase.

Any glucosidase inhibitor can be used in combination with a compound ofthe present invention. A glucosidase inhibitor inhibits the enzymatichydrolysis of complex carbohydrates by glycoside hydrolases, for exampleamylase or maltase, into bioavailable simple sugars, for example,glucose. The rapid metabolic action of glucosidases, particularlyfollowing the intake of high levels of carbohydrates, results in a stateof alimentary hyperglycemia which, in adipose or diabetic subjects,leads to enhanced secretion of insulin, increased fat synthesis and areduction in fat degradation. Following such hyperglycemias,hypoglycemia frequently occurs, due to the augmented levels of insulinpresent. Additionally, it is known chyme remaining in the stomachpromotes the production of gastric juice, which initiates or favors thedevelopment of gastritis or duodenal ulcers. Accordingly, glucosidaseinhibitors are known to have utility in accelerating the passage ofcarbohydrates through the stomach and inhibiting the absorption ofglucose from the intestine. Furthermore, the conversion of carbohydratesinto lipids of the fatty tissue and the subsequent incorporation ofalimentary fat into fatty tissue deposits is accordingly reduced ordelayed, with the concomitant benefit of reducing or preventing thedeleterious abnormalities resulting therefrom. Such glucosidaseinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., Biochemistry, 8:4214 (1969)). Agenerally preferred glucosidase inhibitor includes an amylase inhibitor.An amylase inhibitor is a glucosidase inhibitor that inhibits theenzymatic degradation of starch or glycogen into maltose. Such amylaseinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., Meth. Enzymol., 1:149 (1955)). Theinhibition of such enzymatic degradation is beneficial in reducingamounts of bioavailable sugars, including glucose and maltose, and theconcomitant deleterious conditions resulting therefrom.

A variety of glucosidase inhibitors are known to one of ordinary skillin the art and examples are provided below. Preferred glucosidaseinhibitors are those inhibitors that are selected from the groupconsisting of acarbose, adiposine, voglibose, miglitol, emiglitate,camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. Theglucosidase inhibitor, acarbose, and the various amino sugar derivativesrelated thereto are disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S.Pat. No. 4,254,256. The glucosidase inhibitor, voglibose,3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositoland the various N-substituted pseudo-aminosugars related thereto, aredisclosed in U.S. Pat. No. 4,701,559. The glucosidase inhibitor,miglitol,(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol,and the various 3,4,5-trihydroxypiperidines related thereto, aredisclosed in U.S. Pat. No. 4,639,436. The glucosidase inhibitor,emiglitate, ethylp-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate,the various derivatives related thereto and pharmaceutically acceptableacid addition salts thereof, are disclosed in U.S. Pat. No. 5,192,772.The glucosidase inhibitor, MDL-25637,2,6-dideoxy-7-O-β-D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol,the various homodisaccharides related thereto and the pharmaceuticallyacceptable acid addition salts thereof, are disclosed in U.S. Pat. No.4,634,765. The glucosidase inhibitor, camiglibose, methyl6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-(α-D-glucopyranosidesesquihydrate, the deoxy-nojirimycin derivatives related thereto, thevarious pharmaceutically acceptable salts thereof and synthetic methodsfor the preparation thereof, are disclosed in U.S. Pat. Nos. 5,157,116and 5,504,078. The glycosidase inhibitor, salbostatin and the variouspseudosaccharides related thereto, are disclosed In U.S. Pat. No.5,091,524.

A variety of amylase inhibitors are known to one of ordinary skill inthe art. The amylase inhibitor, tendamistat and the various cyclicpeptides related thereto, are disclosed in U.S. Pat. No. 4,451,455. Theamylase inhibitor AI-3688 and the various cyclic polypeptides relatedthereto are disclosed in U.S. Pat. No. 4,623,714. The amylase inhibitor,trestatin, consisting of a mixture of trestatin A, trestatin B andtrestatin C and the various trehalose-containing aminosugars relatedthereto are disclosed in U.S. Pat. No. 4,273,765.

Additional anti-diabetic compounds, which can be used as the secondagent in combination with a compound of the present invention, include,for example, the following: biguanides (e.g., metformin), insulinsecretagogues (e.g., sulfonylureas and glinides), glitazones,non-glitazone PPARγ agonists, PPARP agonists, inhibitors of DPP-IV,inhibitors of PDES5, inhibitors of GSK-3, glucagon antagonists,inhibitors of f-1,6-BPase(Metabasis/Sankyo), GLP-1/analogs (AC 2993,also known as exendin-4), insulin and insulin mimetics (Merck naturalproducts). Other examples would include PKC-β inhibitors and AGEbreakers.

The compounds of the present invention can be used in combination withanti-obesity agents. Any anti-obesity agent can be used as the secondagent in such combinations and examples are provided herein. Suchanti-obesity activity is readily determined by those skilled in the artaccording to standard assays known in the art.

Suitable anti-obesity agents include phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, β₃ adrenergic receptor agonists,apolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR-4-agonists, cholecystokinin-A (CCK-A)agonists, monoamine reuptake inhibitors (e.g., sibutramine),sympathomimetic agents, serotoninergic agents, cannabinoid receptor(CB-1) antagonists (e.g., rimonabant described in U.S. Pat. No.5,624,941 (SR-141,716A), purine compounds, such as those described in USPatent Publication No. 2004/0092520; pyrazolo[1,5-a][1,3,5]triazinecompounds, such as those described in U.S. Non-Provisional patentapplication Ser. No. 10/763,105; and bicyclic pyrazolyl and imidazolylcompounds, such as those described in U.S. Provisional Application No.60/518,280, dopamine agonists (e.g., bromocriptine),melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin receptor agonists, galanin antagonists, lipaseinhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesinagonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Yantagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones oranalogs thereof, glucocorticoid receptor agonists or antagonists, orexinreceptor antagonists, urocortin binding protein antagonists,glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors(e.g., Axokine™), human agouti-related proteins (AGRP), ghrelin receptorantagonists, histamine 3 receptor antagonists or inverse agonists,neuromedin U receptor agonists, and the like. Rimonabant (SR-141,716Aalso known under the trade name Acomplia™ available from Sanofi-Aventis)can be prepared as described in U.S. Pat. No. 5,624,941. Other suitableCB-1 antagonists include those described in U.S. Pat. Nos. 5,747,524,6,432,984 and 6,518,264; U.S. Patent Publication Nos. US2004/0092520,US2004/0157839, US2004/0214855, and US2004/0214838; U.S. patentapplication Ser. No. 10/971,599; and PCT Patent Publication Nos. WO02/076949, WO 031075660, WO 04/048317, WO 04/013120, and WO 04/012671.

Preferred apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors for use as anti-obesity agents aregut-selective MTP inhibitors, such as dirlotapide described in U.S. Pat.No. 6,720,351;4-(4-(4-(4-((2-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-sec-butyl-2H-1,2,4-triazol-3(4H)-one(R₁₀₃₇₅₇) described in U.S. Pat. Nos. 5,521,186 and 5,929,075; andimplitapide (BAY 13-9952) described in U.S. Pat. No. 6,265,431. As usedherein, the term “gut-selective” means that the MTP Inhibitor has ahigher exposure to the gastro-intestinal tissues versus systemicexposure.

Any thyromimetic can be used as the second agent in combination with acompound of the present Invention. Such thyromimetic activity is readilydetermined by those skilled in the art according to standard assays(e.g., Atherosclerosis, 126: 53-63 (1996)). A variety of thyromimeticagents are known to those skilled in the art, for example thosedisclosed in U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; 5,061,798;5,284,971; 5,401,772; 5,654,468; and 5,569,674. Other antiobesity agentsinclude sibutramine which can be prepared as described in U.S. Pat. No.4,929,629 and bromocriptine which can be prepared as described in U.S.Pat. Nos. 3,752,814 and 3,752,888.

The compounds of the present invention can also be used in combinationwith other antihypertensive agents. Any anti-hypertensive agent can beused as the second agent in such combinations and examples are providedherein. Such antihypertensive activity is readily determined by thoseskilled in the art according to standard assays (e.g., blood pressuremeasurements).

Examples of presently marketed products containing antihypertensiveagents include calcium channel blockers, such as Cardizem®, Adalat®,Calan®, Cardene®, Covera®, Dilacor®, DynaCirc®, Procardia XL®, Sular®,Tiazac®, Vascor®, Verelan®, Isoptin®, Nimotop®, Norvasc®, and Plendile;angiotensin converting enzyme (ACE) inhibitors, such as Accupril®,Altace®, Captopril®, Lotensin®, Mavik®, Monopril®, Prinivil®, Univasc®,Vasotec® and Zestril®.

Amlodipine and related dihydropyridine compounds are disclosed in U.S.Pat. No. 4,572,909, as potent anti-ischemic and antihypertensive agents.U.S. Pat. No. 4,879,303 discloses amlodipine benzenesulfonate salt (alsotermed amlodipine besylate). Amlodipine and amlodipine besylate arepotent and long lasting calcium channel blockers. As such, amlodipine,amlodipine besylate, amlodipine maleate and other pharmaceuticallyacceptable acid addition salts of amlodipine have utility asantihypertensive agents and as antiischemic agents. Amlodipine besylateis currently sold as Norvasc®.

Calcium channel blockers which are within the scope of this inventioninclude, but are not limited to: bepridil, which may be prepared asdisclosed in U.S. Pat. No. 3,962,238 or U.S. Reissue No. 30,577;clentiazem, which may be prepared as disclosed in U.S. Pat. No.4,567,175; diltiazem, fendiline, which may be prepared as disclosed inU.S. Pat. No. 3,262,977; gallopamil, which may be prepared as disclosedin U.S. Pat. No. 3,261,859; mibefradil, which may be prepared asdisclosed in U.S. Pat. No. 4,808,605; prenylamine, which may be preparedas disclosed in U.S. Pat. No. 3,152,173; semotiadil, which may beprepared as disclosed in U.S. Pat. No. 4,786,635; terodiline, which maybe prepared as disclosed in U.S. Pat. No. 3,371,014; verapamil, whichmay be prepared as disclosed in U.S. Pat. No. 3,261,859; aranipine,which may be prepared as disclosed in U.S. Pat. No. 4,572,909;barnidipine, which may be prepared as disclosed in U.S. Pat. No.4,220,649; benidipine, which may be prepared as disclosed in EuropeanPatent Application Publication No. 106,275; cilnidipine, which may beprepared as disclosed in U.S. Pat. No. 4,672,068; efonidipine, which maybe prepared as disclosed in U.S. Pat. No. 4,885,284; elgodipine, whichmay be prepared as disclosed in U.S. Pat. No. 4,952,592; felodipine,which may be prepared as disclosed in U.S. Pat. No. 4,264,611;isradipine, which may be prepared as disclosed in U.S. Pat. No.4,466,972; lacidipine, which may be prepared as disclosed in U.S. Pat.No. 4,801,599; lercanidipine, which may be prepared as disclosed in U.S.Pat. No. 4,705,797; manidipine, which may be prepared as disclosed inU.S. Pat. No. 4,892,875; nicardipine, which may be prepared as disclosedin U.S. Pat. No. 3,985,758; nifedipine, which may be prepared asdisclosed in U.S. Pat. No. 3,485,847; nilvadipine, which may be preparedas disclosed in U.S. Pat. No. 4,338,322; nimodipine, which may beprepared as disclosed in U.S. Pat. No. 3,799,934; nisoldipine, which maybe prepared as disclosed in U.S. Pat. No. 4,154,839; nitrendipine, whichmay be prepared as disclosed in U.S. Pat. No. 3,799,934; cinnarizine,which may be prepared as disclosed in U.S. Pat. No. 2,882,271;flunarizine, which may be prepared as disclosed in U.S. Pat. No.3,773,939; lidoflazine, which may be prepared as disclosed in U.S. Pat.No. 3,267,104; lomerizine, which may be prepared as disclosed in U.S.Pat. No. 4,663,325; bencyclane, which may be prepared as disclosed inHungarian Patent No. 151,865; etafenone, which may be prepared asdisclosed in German Patent No. 1,265,758; and perhexyline, which may beprepared as disclosed in British Patent No. 1,025,578.

Angiotensin Converting Enzyme Inhibitors (ACE-Inhibitors) which arewithin the scope of this invention include, but are not limited to:alacepril, which may be prepared as disclosed in U.S. Pat. No.4,248,883; benazepril, which may be prepared as disclosed in U.S. Pat.No. 4,410,520; captopril, which may be prepared as disclosed in U.S.Pat. Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared asdisclosed in U.S. Pat. No. 4,462,790; delapril, which may be prepared asdisclosed in U.S. Pat. No. 4,385,051; enalapril, which may be preparedas disclosed in U.S. Pat. No. 4,374,829; fosinopril, which may beprepared as disclosed in U.S. Pat. No. 4,337,201; imadapril, which maybe prepared as disclosed in U.S. Pat. No. 4,508,727; lisinopril, whichmay be prepared as disclosed in U.S. Pat. No. 4,555,502; moveltopril,which may be prepared as disclosed in Belgian Patent No. 893,553;perindopril, which may be prepared as disclosed in U.S. Pat. No.4,508,729; quinapril, which may be prepared as disclosed in U.S. Pat.No. 4,344,949; ramipril, which may be prepared as disclosed in U.S. Pat.No. 4,587,258; spirapril, which may be prepared as disclosed in U.S.Pat. No. 4,470,972; temocapril, which may be prepared as disclosed inU.S. Pat. No. 4,699,905; and trandolapril, which may be prepared asdisclosed in U.S. Pat. No. 4,933,361.

Angiotensin-II receptor antagonists (A-II antagonists) which are withinthe scope of this invention include, but are not limited to:candesartan, which may be prepared as disclosed in U.S. Pat. No.5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat.No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S.Pat. No. 5,270,317; losartan, which may be prepared as disclosed in U.S.Pat. No. 5,138,069; and valsartan, which may be prepared as disclosed inU.S. Pat. No. 5,399,578.

Beta-adrenergic receptor blockers (beta- or β-blockers) which are withinthe scope of this invention include, but are not limited to: acebutolol,which may be prepared as disclosed in U.S. Pat. No. 3,857,952;alprenolol, which may be prepared as disclosed in Netherlands PatentApplication No. 6,605,692; amosulalol, which may be prepared asdisclosed in U.S. Pat. No. 4,217,305; arotinolol, which may be preparedas disclosed in U.S. Pat. No. 3,932,400; atenolol, which may be preparedas disclosed in U.S. Pat. No. 3,663,607 or 3,836,671; befunolol, whichmay be prepared as disclosed in U.S. Pat. No. 3,853,923; betaxolol,which may be prepared as disclosed in U.S. Pat. No. 4,252,984;bevantolol, which may be prepared as disclosed in U.S. Pat. No.3,857,981; bisoprolol, which may be prepared as disclosed in U.S. Pat.No. 4,171,370; bopindolol, which may be prepared as disclosed in U.S.Pat. No. 4,340,541; bucumolol, which may be prepared as disclosed inU.S. Pat. No. 3,663,570; bufetolol, which may be prepared as disclosedin U.S. Pat. No. 3,723,476; bufuralol, which may be prepared asdisclosed in U.S. Pat. No. 3,929,836; bunitrolol, which may be preparedas disclosed in U.S. Pat. Nos. 3,940,489 and 3,961,071; buprandolol,which may be prepared as disclosed in U.S. Pat. No. 3,309,406;butiridine hydrochloride, which may be prepared as disclosed in FrenchPatent No. 1,390,056; butofilolol, which may be prepared as disclosed inU.S. Pat. No. 4,252,825; carazolol, which may be prepared as disclosedin German Patent No. 2,240,599; carteolol, which may be prepared asdisclosed in U.S. Pat. No. 3,910,924; carvedilol, which may be preparedas disclosed in U.S. Pat. No. 4,503,067; celiprolol, which may beprepared as disclosed in U.S. Pat. No. 4,034,009; cetamolol, which maybe prepared as disclosed in U.S. Pat. No. 4,059,622; cloranolol, whichmay be prepared as disclosed in German Patent No. 2,213,044; dilevalol,which may be prepared as disclosed in Clifton et al., J. Med. Chem.,25:670 (1982); epanolol, which may be prepared as disclosed in EuropeanPatent Publication Application No. 41,491; indenolol, which may beprepared as disclosed in U.S. Pat. No. 4,045,482; labetalol, which maybe prepared as disclosed in U.S. Pat. No. 4,012,444; levobunolol, whichmay be prepared as disclosed in U.S. Pat. No. 4,463,176; mepindolol,which may be prepared as disclosed in Seeman et al., Heir. Chim. Acta,54:241 (1971); metipranolol, which may be prepared as disclosed inCzechoslovakian Patent Application No. 128,471; metoprolol, which may beprepared as disclosed in U.S. Pat. No. 3,873,600; moprolol, which may beprepared as disclosed in U.S. Pat. No. 3,501,7691; nadolol, which may beprepared as disclosed in U.S. Pat. No. 3,935,267; nadoxolol, which maybe prepared as disclosed in U.S. Pat. No. 3,819,702; nebivalol, whichmay be prepared as disclosed in U.S. Pat. No. 4,654,362; nipradilol,which may be prepared as disclosed in U.S. Pat. No. 4,394,382;oxprenolol, which may be prepared as disclosed in British Patent No.1,077,603; perbutolol, which may be prepared as disclosed in U.S. Pat.No. 3,551,493; pindolol, which may be prepared as disclosed in SwissPatent Nos. 469,002 and 472,404; practolol, which may be prepared asdisclosed in U.S. Pat. No. 3,408,387; pronethalol, which may be preparedas disclosed in British Patent No. 909,357; propranolol, which may beprepared as disclosed in U.S. Pat. Nos. 3,337,628 and 3,520,919;sotalol, which may be prepared as disclosed in Uloth et al., J. Med.Chem., 9:88 (1966); sufinalol, which may be prepared as disclosed inGerman Patent No. 2,728,641; talindol, which may be prepared asdisclosed in U.S. Pat. Nos. 3,935,259 and 4,038,313; tertatolol, whichmay be prepared as disclosed in U.S. Pat. No. 3,960,891; tilisolol,which may be prepared as disclosed in U.S. Pat. No. 4,129,565; timolol,which may be prepared as disclosed in U.S. Pat. No. 3,655,663;toliprolol, which may be prepared as disclosed in U.S. Pat. No.3,432,545; and xibenolol, which may be prepared as disclosed in U.S.Pat. No. 4,018,824.

Alpha-adrenergic receptor blockers (alpha- or α-blockers) which arewithin the scope of this invention include, but are not limited to:amosulalol, which may be prepared as disclosed in U.S. Pat. No.4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat.No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S.Pat. No. 4,252,721; doxazosin, which may be prepared as disclosed inU.S. Pat. No. 4,188,390; fenspiride, which may be prepared as disclosedin U.S. Pat. No. 3,399,192; indoramin, which may be prepared asdisclosed in U.S. Pat. No. 3,527,761; labetolol; naftopidil, which maybe prepared as disclosed in U.S. Pat. No. 3,997,666; nicergoline, whichmay be prepared as disclosed in U.S. Pat. No. 3,228,943; prazosin, whichmay be prepared as disclosed in U.S. Pat. No. 3,511,836; tamsulosin,which may be prepared as disclosed in U.S. Pat. No. 4,703,063;tolazoline, which may be prepared as disclosed in U.S. Pat. No.2,161,938; trimazosin, which may be prepared as disclosed in U.S. Pat.No. 3,669,968; and yohimbine, which may be isolated from natural sourcesaccording to methods well known to those skilled in the art.

The term “vasodilator,” where used herein, is meant to include cerebralvasodilators, coronary vasodilators and peripheral vasodilators.Cerebral vasodilators within the scope of this invention include, butare not limited to: bencyclane; cinnarizine; citicoline, which may beisolated from natural sources as disclosed in Kennedy et al., J. Am.Chem. Soc., 77:250 (1955) or synthesized as disclosed in Kennedy, J.Biol. Chem., 222:185 (1956); cyclandelate, which may be prepared asdisclosed in U.S. Pat. No. 3,663,597; ciclonicate, which may be preparedas disclosed in German Patent No, 1,910,481; diisopropylaminedichloroacetate, which may be prepared as disclosed in British PatentNo. 862,248; eburnamonine, which may be prepared as disclosed in Hermannet al., J. Am. Chem. Soc., 101:1540 (1979); fasudil, which may beprepared as disclosed in U.S. Pat. No. 4,678,783; fenoxedil, which maybe prepared as disclosed in U.S. Pat. No. 3,818,021; flunarizine, whichmay be prepared as disclosed in U.S. Pat. No. 3,773,939; ibudilast,which may be prepared as disclosed in U.S. Pat. No. 3,850,941;ifenprodil, which may be prepared as disclosed in U.S. Pat. No.3,509,164; lomerizine, which may be prepared as disclosed in U.S. Pat.No. 4,663,325; nafronyl, which may be prepared as disclosed in U.S. Pat.No. 3,334,096; nicametate, which may be prepared as disclosed in Blickeet al., J. Am. Chem. Soc., 64:1722 (1942); nicergoline, which may beprepared as disclosed above; nimodipine, which may be prepared asdisclosed in U.S. Pat. No. 3,799,934; papaverine, which may be preparedas reviewed in Goldberg, Chem. Prod. Chem. News, 17:371 (1954);pentifylline, which may be prepared as disclosed in German Patent No.860,217; tinofedrine, which may be prepared as disclosed in U.S. Pat.No. 3,563,997; vincamine, which may be prepared as disclosed in U.S.Pat. No. 3,770,724; vinpocetine, which may be prepared as disclosed inU.S. Pat. No. 4,035,750; and viquidil, which may be prepared asdisclosed in U.S. Pat. No. 2,500,444.

Coronary vasodilators within the scope of this invention include, butare not limited to: amotriphene, which may be prepared as disclosed inU.S. Pat. No. 3,010,965; bendazol, which may be prepared as disclosed inJ. Chem. Soc., 2426 (1958); benfurodil hemisuccinate, which may beprepared as disclosed in U.S. Pat. No. 3,355,463; benziodarone, whichmay be prepared as disclosed in U.S. Pat. No. 3,012,042; chloracizine,which may be prepared as disclosed in British Patent No. 740,932;chromonar, which may be prepared as disclosed in U.S. Pat. No.3,282,938; clobenfural, which may be prepared as disclosed in BritishPatent No. 1,160,925; clonitrate, which may be prepared from propanediolaccording to methods well known to those skilled in the art, e.g., seeAnnalen, 1870, 155, 165; cloricromen, which may be prepared as disclosedin U.S. Pat. No. 4,452,811; dilazep, which may be prepared as disclosedin U.S. Pat. No. 3,532,685; dipyridamole, which may be prepared asdisclosed in British Patent No. 807,826; droprenilamine, which may beprepared as disclosed in German Patent No. 2,521,113; efloxate, whichmay be prepared as disclosed in British Patent Nos. 803,372 and 824,547;erythrityl tetranitrate, which may be prepared by nitration oferythritol according to methods well-known to those skilled in the art;etafenone, which may be prepared as disclosed in German Patent No.1,265,758; fendiline, which may be prepared as disclosed in U.S. Pat.No. 3,262,977; floredil, which may be prepared as disclosed in GermanPatent No. 2,020,464; ganglefene, which may be prepared as disclosed inU.S.S.R. Patent No. 115,905; hexestrol, which may be prepared asdisclosed in U.S. Pat. No. 2,357,985; hexobendine, which may be preparedas disclosed in U.S. Pat. No. 3,267,103; itramin tosylate, which may beprepared as disclosed in Swedish Patent No. 168,308; khellin, which maybe prepared as disclosed in Baxter et al., J. Chem. Soc., 1949, S 30;lidoflazine, which may be prepared as disclosed in U.S. Pat. No.3,267,104; mannitol hexanitrate, which may be prepared by the nitrationof mannitol according to methods well-known to those skilled in the art;medibazine, which may be prepared as disclosed in U.S. Pat. No.3,119,826; nitroglycerin; pentaerythritol tetranitrate, which may beprepared by the nitration of pentaerythritol according to methodswell-known to those skilled in the art; pentrinitrol, which may beprepared as disclosed in German Patent No. 638, 422-3; perhexylline,which may be prepared as disclosed above; pimethylline, which may beprepared as disclosed in U.S. Pat. No. 3,350,400; prenylamine, which maybe prepared as disclosed in U.S. Pat. No. 3,152,173; propatyl nitrate,which may be prepared as disclosed in French Patent No. 1,103,113;trapidil, which may be prepared as disclosed in East German Patent No.55,956; tricromyl, which may be prepared as disclosed in U.S. Pat. No.2,769,015; trimetazidine, which may be prepared as disclosed in U.S.Pat. No. 3,262,852; trolnitrate phosphate, which may be prepared bynitration of triethanolamine followed by precipitation with phosphoricacid according to methods well-known to those skilled in the art;visnadine, which may be prepared as disclosed in U.S. Pat. Nos.2,816,118 and 2,980,699.

Peripheral vasodilators within the scope of this invention include, butare not limited to: aluminum nicotinate, which may be prepared asdisclosed in U.S. Pat. No. 2,970,082; bamethan, which may be prepared asdisclosed in Corrigan et al., J. Am. Chem. Soc., 67:1894 (1945);bencyclane, which may be prepared as disclosed above; betahistine, whichmay be prepared as disclosed in Walter et al., J. Am. Chem. Soc.,63:2771 (1941); bradykinin, which may be prepared as disclosed inHamburg et al., Arch. Biochem. Biophys., 76:252 (1958); brovincamine,which may be prepared as disclosed in U.S. Pat. No. 4,146,643;bufeniode, which may be prepared as disclosed in U.S. Pat. No.3,542,870; buflomedil, which may be prepared as disclosed in U.S. Pat.No. 3,895,030; butalamine, which may be prepared as disclosed in U.S.Pat. No. 3,338,899; cetiedil, which may be prepared as disclosed inFrench Patent No. 1,460,571; ciclonicate, which may be prepared asdisclosed in German Patent No, 1,910,481; cinepazide, which may beprepared as disclosed in Belgian Patent No. 730,345; cinnarizine, whichmay be prepared as disclosed above; cyclandelate, which may be preparedas disclosed above; diisopropylamine dichloroacetate, which may beprepared as disclosed above; eledoisin, which may be prepared asdisclosed in British Patent No. 984,810; fenoxedil, which may beprepared as disclosed above; flunarizine, which may be prepared asdisclosed above; hepronicate, which may be prepared as disclosed in U.S.Pat. No. 3,384,642; ifenprodil, which may be prepared as disclosedabove; iloprost, which may be prepared as disclosed in U.S. Pat. No.4,692,464; inositol niacinate, which may be prepared as disclosed inBadgett et al., J. Am. Chem. Soc., 69:2907 (1947); isoxsuprine, whichmay be prepared as disclosed in U.S. Pat. No. 3,056,836; kallidin, whichmay be prepared as disclosed in Biochem. Biophys. Res. Commun., 6:210(1961); kallikrein, which may be prepared as disclosed in German PatentNo. 1,102,973; moxisylyte, which may be prepared as disclosed in GermanPatent No. 905,738; nafronyl, which may be prepared as disclosed above;nicametate, which may be prepared as disclosed above; nicergoline, whichmay be prepared as disclosed above; nicofuranose, which may be preparedas disclosed in Swiss Patent No. 366,523; nylidrin, which may beprepared as disclosed in U.S. Pat. Nos. 2,661,372 and 2,661,373;pentifylline, which may be prepared as disclosed above; pentoxifylline,which may be prepared as disclosed in U.S. Pat. No. 3,422,107;piribedil, which may be prepared as disclosed in U.S. Pat. No.3,299,067; prostaglandin E₁, which may be prepared by any of the methodsreferenced in the Merck Index, Twelfth Edition, Budaveri, Ed., NewJersey, p. 1353 (1996); suloctidil, which may be prepared as disclosedin German Patent No. 2,334,404; tolazoline, which may be prepared asdisclosed in U.S. Pat. No. 2,161,938; and xanthinol niacinate, which maybe prepared as disclosed in German Patent No. 1,102,750.

The term “diuretic,” within the scope of this invention, is meant toinclude diuretic benzothiadiazine derivatives, diureticorganomercurials, diuretic purines, diuretic steroids, diureticsulfonamide derivatives, diuretic uracils and other diuretics such asamanozine, which may be prepared as disclosed in Austrian Patent No.168,063; amiloride, which may be prepared as disclosed in Belgian PatentNo. 639,386; arbutin, which may be prepared as disclosed inTschitschibabin, Annalen, 1930, 479, 303; chlorazanil, which may beprepared as disclosed in Austrian Patent No. 168,063; ethacrynic acid,which may be prepared as disclosed in U.S. Pat. No. 3,255,241; etozolin,which may be prepared as disclosed in U.S. Pat. No. 3,072,653;hydracarbazine, which may be prepared as disclosed in British Patent No.856,409; isosorbide, which may be prepared as disclosed in U.S. Pat. No.3,160,641; mannitol; metochalcone, which may be prepared as disclosed inFreudenberg et al., Ber., 1957, 90, 957; muzolimine, which may beprepared as disclosed in U.S. Pat. No. 4,018,890; perhexyline, which maybe prepared as disclosed above; ticrynafen, which may be prepared asdisclosed in U.S. Pat. No. 3,758,506; triamterene which may be preparedas disclosed in U.S. Pat. No. 3,051,230; and urea.

Diuretic benzothiadiazine derivatives within the scope of this inventioninclude, but are not limited to: althiazide, which may be prepared asdisclosed in British Patent No. 902,658; bendroflumethiazide, which maybe prepared as disclosed in U.S. Pat. No. 3,265,573; benzthiazide,McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959),Abstract of papers, pp 13-O; benzylhydrochlorothiazide, which may beprepared as disclosed in U.S. Pat. No. 3,108,097; buthiazide, which maybe prepared as disclosed in British Patent Nos. 861,367 and 885,078;chlorothiazide, which may be prepared as disclosed in U.S. Pat. Nos.2,809,194 and 2,937,169; chlorthalidone, which may be prepared asdisclosed in U.S. Pat. No. 3,055,904; cyclopenthiazide, which may beprepared as disclosed in Belgian Patent No. 587,225; cyclothiazide,which may be prepared as disclosed in Whitehead et al., J. Org. Chem.,26:2814 (1961); epithiazide, which may be prepared as disclosed in U.S.Pat. No. 3,009,911; ethiazide, which may be prepared as disclosed inBritish Patent No. 861,367; fenquizone, which may be prepared asdisclosed in U.S. Pat. No. 3,870,720; indapamide, which may be preparedas disclosed in U.S. Pat. No. 3,565,911; hydrochlorothiazide, which maybe prepared as disclosed in U.S. Pat. No. 3,164,588; hydroflumethiazide,which may be prepared as disclosed in U.S. Pat. No. 3,254,076;methyclothiazide, which may be prepared as disclosed in Close et al, J.Am. Chem. Soc., 82:1132 (1960); meticrane, which may be prepared asdisclosed in French Patent Nos. M2790 and 1,365,504; metolazone, whichmay be prepared as disclosed in U.S. Pat. No. 3,360,518; paraflutizide,which may be prepared as disclosed in Belgian Patent No. 620,829;polythiazide, which may be prepared as disclosed in U.S. Pat. No.3,009,911; quinethazone, which may be prepared as disclosed in U.S. Pat.No. 2,976,289; teclothiazide, which may be prepared as disclosed inClose et al., J. Am. Chem. Soc., 82:1132 (1960); and trichlormethiazide,which may be prepared as disclosed in deStevens et al., Experientia,16:113 (1960).

Diuretic sulfonamide derivatives within the scope of this inventioninclude, but are not limited to: acetazolamide, which may be prepared asdisclosed in U.S. Pat. No. 2,980,679; ambuside, which may be prepared asdisclosed in U.S. Pat. No. 3,188,329; azosemide, which may be preparedas disclosed in U.S. Pat. No. 3,665,002; bumetanide, which may beprepared as disclosed in U.S. Pat. No. 3,634,583; butazolamide, whichmay be prepared as disclosed in British Patent No. 769,757;chloraminophenamide, which may be prepared as disclosed in U.S. Pat.Nos. 2,809,194, 2,965,655 and 2,965,656; clofenamide, which may beprepared as disclosed in Olivier, Rec. Trav. Chim., 1918, 37, 307;clopamide, which may be prepared as disclosed in U.S. Pat. No.3,459,756; clorexolone, which may be prepared as disclosed in U.S. Pat.No. 3,183,243; disulfamide, which may be prepared as disclosed inBritish Patent No. 851,287; ethoxolamide, which may be prepared asdisclosed in British Patent No. 795,174; furosemide, which may beprepared as disclosed in U.S. Pat. No. 3,058,882; mefruside, which maybe prepared as disclosed in U.S. Pat. No. 3,356,692; methazolamide,which may be prepared as disclosed in U.S. Pat. No. 2,783,241;piretanide, which may be prepared as disclosed in U.S. Pat. No.4,010,273; torasemide, which may be prepared as disclosed in U.S. Pat.No. 4,018,929; tripamide, which may be prepared as disclosed in JapanesePatent No. 73 05,585; and xipamide, which may be prepared as disclosedin U.S. Pat. No. 3,567,777.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture, in the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated. The elderly are atgreatest risk of osteoporosis, and the problem is therefore predicted toincrease significantly within the aging of the population. Worldwidefracture incidence is forecasted to increase three-fold over the next 60years, and one study has estimated that there will be 4.5 million hipfractures worldwide in 2050. Women are at greater risk of osteoporosisthan men. Women experience a sharp acceleration of bone loss during thefive years following menopause. Other factors that increase the riskinclude smoking, alcohol abuse, a sedentary lifestyle and low calciumintake.

Those skilled in the art will recognize that anti-resorptive agents (forexample progestins, polyphosphonates, bisphosphonate(s), estrogenagonists/antagonists, estrogen, estrogen/progestin combinations,Premarin®, estrone, estriol or 17α- or 17β-ethynyl estradiol) may beused in conjunction with the compounds of the present invention.

Exemplary progestins are available from commercial sources and include:algestone acetophenide, altrenogest, amadinone acetate, anagestoneacetate, chlormadinone acetate, cingestol, clogestone acetate,clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone,dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel,fluorogestone acetate, gestaclone, gestodene, gestonorone caproate,gestrinone, haloprogesterone, hydroxyprogesterone caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenproprionate, progesterone, quingestanolacetate, quingestrone, and tigestol. Preferred progestins aremedroxyprogestrone, norethindrone and norethynedrel.

Exemplary bone resorption inhibiting polyphosphonates includepolyphosphenates of the type disclosed in U.S. Pat. No. 3,683,080.Preferred polyphosphonates are geminal diphosphonates (also referred toas bis-phosphonates). Tiludronate disodium is an especially preferredpolyphosphonata. Ibandronic acid is an especially preferredpolyphosphonate. Alendronate and resindronate are especially preferredpolyphosphonates. Zoledronic acid is an especially preferredpolyphosphonate. Other preferred polyphosphonates are6-amino-1-hydroxy-hexylidene-bisphosphonic acid and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Thepolyphosphonates may be administered in the form of the acid, or of asoluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonicacid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid, N,N-dimethylamino methane diphosphonicacid, N-(2-hydroxyethyl)amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with amammalian estrogen agonist/antagonist. Any estrogen agonist/antagonistmay be used in the combination aspect of this invention. The termestrogen agonist/antagonist refers to compounds which bind with theestrogen receptor, inhibit bone turnover and/or prevent bone loss. Inparticular, estrogen agonists are herein defined as chemical compoundscapable of binding to the estrogen receptor sites in mammalian tissue,and mimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art of standard assays includingestrogen receptor binding assays, standard bone histomorphometric anddensitometer methods (Eriksen E. F. et al., Bone Histomorphometry, RavenPress, New York, pp. 1-74 (1994); Grier, S. J. et al., “The Use ofDual-Energy X-Ray Absorptiometry In Animals”, Inv. Radiol., 31(1):50-62(1996); Wahner H. W. et al., The Evaluation of Osteoporosis: Dual EnergyX-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London,pp. 1-296 (1994)). A variety of these compounds are described andreferenced below. Another preferred estrogen agonist/antagonist is3-(4-{1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid, which is disclosedin Willson et al., Endocrinology, 138:3901-3911 (1997). Anotherpreferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-(-4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and related compounds whichare disclosed in U.S. Pat. No. 4,536,516. Another related compound is4-hydroxy tamoxifen, which is disclosed in U.S. Pat. No. 4,623,660. Apreferred estrogen agonist/antagonist is raloxifene: (methanone,(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)hydrochloride)which is disclosed in U.S. Pat. No. 4,418,068. Another preferredestrogen agonist/antagonist is toremifene: (ethanamine,2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S.Pat. No. 4,996,225. Another preferred estrogen agonist/antagonist iscentchroman: 1-(2-((4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which isdisclosed in U.S. Pat. No. 3,822,287. Also preferred is levormeloxifene.Another preferred estrogen agonist/antagonist is idoxifene:(E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone,which is disclosed in U.S. Pat. No. 4,839,155. Another preferredestrogen agonist/antagonist is2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olwhich is disclosed in U.S. Pat. No. 5,488,058. Another preferredestrogen agonist/antagonist is6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol,which is disclosed in U.S. Pat. No. 5,484,795. Another preferredestrogen agonist/antagonist is(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)-methanonewhich is disclosed, along with methods of preparation, in PCTPublication No. WO 95/10513. Other preferred estrogenagonist/antagonists include the compounds, TSE-424 (Wyeth-AyerstLaboratories) and arazoxifene.

Other preferred estrogen agonist/antagonists include compounds asdescribed in U.S. Pat. No. 5,552,412. Especially preferred compoundsdescribed therein are:cis-6-(′4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol(also known as lasofoxifene);cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;cis-1-(6′-pyrrolodinoethoxy-3′-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,44etrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol;and1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814, which discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

Other anti-osteoporosis agents, which can be used as the second agent incombination with a compound of the present invention, include, forexample, the following: parathyroid hormone (PTH) (a bone anabolicagent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Pat.No. 6,132,774), particularly calcium receptor antagonists; calcitonin;vitamin D and vitamin D analogs.

Any selective androgen receptor modulator (SARM) can be used incombination with a compound of the present invention. A selectiveandrogen receptor modulator (SARM) is a compound that possessesandrogenic activity and which exerts tissue-selective effects. SARMcompounds can function as androgen receptor agonists, partial agonists,partial antagonists or antagonists. Examples of suitable SARMs includecompounds such as cyproterone acetate, chlormadinone, flutamide,hydroxyflutamide, bicalutamide, nilutamide, spironolactone,4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinoline derivatives,1,2-dihydropyridino[5,6-g]quinoline derivatives andpiperidino[3,2-g]quinolinone derivatives.

Cypterone, also known as(1b,2b)-6-chloro-1,2-dihydro-17-hydroxy-3′H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dioneis disclosed in U.S. Pat. No. 3,234,093. Chlormadinone, also known as17-(acetyloxy)-6-chloropregna-4-,6-diene-3,20-dione, in its acetateform, acts as an anti-androgen and is disclosed in U.S. Pat. No.3,485,852. Nilutamide, also known as5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedioneand by the trade name Nilandron® is disclosed in U.S. Pat. No.4,097,578. Flutamide, also known as2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide and the tradename Eulexin® is disclosed in U.S. Pat. No. 3,847,988. Bicalutamide,also known as4′-cyano-a′,a′,a′-trifluoro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidideand the trade name Casodex is disclosed in EP-100172. The enantiomers ofbiclutamide are discussed by Tucker et al., J. Med. Chem., 31:885-887(1988). Hydroxyflutamide, a known androgen receptor antagonist in mosttissues, has been suggested to function as a SARM for effects on IL-6production by osteoblasts as disclosed in Hofbauer et al., J. BoneMiner. Res., 14:1330-1337 (1999). Additional SARMs have been disclosedin U.S. Pat. No. 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO02/00617, WO 02/16310, U.S. Patent Application Publication No, US2002/0099096, U.S. Patent Application Publication No. US 2003/0022868,WO 03/011302 and WO 03/011824.

Any compound having activity as an LXR modulator can serve as the secondcompound in the combination therapy aspect of the present invention. Theterm LXR modulator refers to compounds that modulate the liver Xreceptor (LXR), which has been identified as a regulator of cellular andwhole body cholesterol metabolism. Such LXR modulation activity isreadily determined by those skilled in the art according to standardassays (e.g., U.S. Pat. No. 6,140,343). A variety of LXR modulators willbe known to those skilled in the art, for example, those disclosed inU.S. Patent Application Publication Nos. 2003/01814206, 2005/0080111,and 2005/0245515.

All of the above referenced patents and patent applications are herebyincorporated by reference herein.

The combinations can be co-formulated or in the form of kits packaged toprovide appropriate dosages for co-administration.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

The following abbreviations are used herein:

-   ee=enantiomeric excess-   DMF=dimethylformamide-   EtOAc=ethyl acetate-   LDA=lithium diisopropylamide-   Hünig's Base=DIEA=iPr₂NEt=N,N-diisopropylethylamine-   Me=methyl-   Et=ethyl-   n-Bu=n-butyl-   Bn=benzyl-   iPr=isopropyl-   Allyl=1-propenyl-   RT=retention time-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TMS=trimethylsilyl-   t-Bu=tert-butyl-   MeI=methyl iodide-   (BOC)₂O=di-tert-butyl dicarbonate-   Ac₂O=acetic anhydride-   TEA=NEt₃=Et₃N=triethylamine-   n-BuLi=n-butyllithium-   rt=room temperature-   LC=liquid chromatography-   Ph=phenyl-   EtOH=ethanol-   BuOH=butan-1-ol-   DCE=dichloroethane-   DMSO=dimethylsulfoxide-   MS=molecular sieves-   MS (ES)=Electro-Spray Mass Spectrometry-   sat=saturated-   AcOH=acetic acid-   MeOH=methanol-   Et₂O=diethyl ether-   Ac=acetyl-   h=hours-   EDCI=water soluble dicarbonyl diimide,    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HOBT=1-hydroxy-benzotriazole-   TBAF=tetrabutylammonium fluoride-   TBAF.3H₂O=tetrabutylammonium fluoride trihydrate-   DMA=dimethylacetamide-   DME=1,2-dimethoxyethane-   HRMS=high resolution mass spectrometry-   TBME=MTBE=methyl tert-butyl ether (i.e., 2-methoxy-2-methyl-propane)-   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphonium    hexafluorophosphate-   DEA=diethylamine-   IPA=isopropylamine-   TMSCl=trimethylsilylchloride-   MS=mass spectrum-   NMR=nuclear magnetic resonance-   TMSI=trimethylsilyliodide-   TMS=trimethylsilyl-   PPA=polyphosphoric acid-   LDA=lithium diisopropylamine-   UV=ultraviolet-   DCM=dichloromethane-   DMAC=N,N-dimethylacetamide-   DAST=diethylaminosulfurtrifluoride-   HPLC=high performance liquid chromatography-   SFC=super critical fluid chromatography-   TBAB=tetrabutylammonium bromide-   ACN=acetonitrile-   IIDQ=polystyrene resin-   TosMIC=tosylmethyl isocyanide-   BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Pd₂ (dba)₃=tris-(dibenzylideneacetone) dipalladium(0)-   Pd(PPh₃)₄=tetrakis(triphenylphosphine) palladium(0)-   [Ir(COD)Cl]₂=Chloro-1,5-cyclooctadiene iridium (I) dimer-   Ar=argon-   TBAB=tetrabutylammonium bromide-   9-BBN=9-borabicyclo[3.3.1]nonane-   DEAD=diethyl azodicarboxylate-   DPPA=diphenyl phosphoryl azide-   NBS=N-bromosuccinimide-   DMAP=4-di(methylamino)pyridine-   LAH=lithium aluminum hydride-   NMP=1-methyl-2-pyrrolidone-   NMM=1-methyl-2-morpholine-   Super-hydride=lithium triethylborohydride-   DIBAL-H=diisobutylaluminium hydride-   Dess-Martin    periodinane=1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one-   Lawesson's    reagent=2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane    2,4-disulfide-   Jones[O]reagent=CrO₃/H₂SO₄/H₂O/acetone-   PCy₃=tricyclohexylphosphine-   Tf₂O=triflic anhydride=trifluoromethanesulfonic anhydride-   Bu₄NBr=tetrabutylammonium bromide-   TBDMSC1=tert-butylchlorodimethylsilane-   TFFH=fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate-   R,R-MnCl    (Salen)=(1R,2R)-(−)-[1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]manganese (III)    chloride-   LiOTf=lithium trifluoromethanesulfonate-   Tf=trifluoromethanesulfonate-   EtAICl₂=ethyl aluminum dichloride-   ZnEt₂=diethyl zinc-   TsOH=4-methylbenzenesulfonic acid-   Ts=4-methylbenzenesulfonate-   n-Bu₂SnO₂=dibutyltin(IV) oxide-   Boc=t-Boc=t-butoxycarbonyl-   Pd(OH)₂/C=palladium (II) hydroxide on carbon-   Pd/C=palladium on carbon-   Fmoc=3,9-fluorenylmethoxycarbonyl-   Cbz=carbobenzoxy-   allylMgBr=1-propenyl magnesium bromide-   diglyme=diethylene glycol dimethyl    ether=1-methoxy-2-(2-methoxyethoxy)ethane-   TBME=tert-butyl methyl ether-   L-proline ═(S)-pyrrolidine-2-carboxylic acid-   P(t-Bu)₃=tri-t-butyl phosphine-   triphosgene=bis(trichloromethyl)carbonate

Specifically exemplified compounds of Formula Ia and Ib are listed alongwith structure, name, HPLC retention time, molecular mass and theprocedure employed to make such examples, in the proceeding text and inthe tables set forth below. The absolute configuration of chiralexamples was assigned by NMR comparison of the intermediatediastereomeric sulfinyl amides, but has not be confirmed bycrystallographic assignment. Enantiomerically pure intermediate amineswere obtained by separation of the racemic mixtures using SFC or by thechiral synthesis described in Procedures 4, 5 and 6.

The chromatography techniques used to determine the compound retentiontimes in the tables are as follows:

(1) LCMS=Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm;

(2) LCMS=Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm;

(3) LCMS=Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min, monitoring at220 nm;

(4) LCMS=Waters Sunfire C18 column, 4.6×50 mm×5 m eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm;

(5) LCMS=YMC ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm;

(6) LC=Chromolith SpeedROD column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm;

(7) LC=Phenomenex Synergi 4u POLAR-RP column, 21.2×100 mm eluting with10-90% ACN/H₂O over 12 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm;

(8) LCMS=Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%ACN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min, monitoring at220 nm;

(9) LC=Chromolith SpeedROD column, 4.6×50 mm eluting with 10-90% ACN/H₂Oover 2 minutes containing 0.2% phosphoric acid, 5 mL/min, monitoring at220 nm;

(10) LCMS=Waters Sunfire C18 column, 4.6×50 mm eluting with 10-90%ACN/H₂O over 4 minutes containing 10 mM NH₄OAc; 4 mL/min, monitoring at220 nm;

(11) LC=Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm;

(12) LCMS=Chromolith Performance RP-18e column, 4.6×100 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% trifluoroacetic acid, 5mL/min, monitoring at 220 nm;

(13) LC=Chromolith Performance RP-18e column, 4.6×100 mm eluting with10-90% acetonitrile/H₂O over 2 minutes containing 0.1% trifluoroaceticacid, 4 mL/min, monitoring at 220 nm;

(14) LCMS=Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%ACN/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm;

(15) LCMS=Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%ACN/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm;

(16) LCMS=Waters Sunfire C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 8 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm.

The molecular mass of the compounds listed in the tables set forth belowwere determined by MS (ES) by the formula m/z.

Example 1

1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)ureaProcedure 1 1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

An ether solution (40 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene(2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at−78° C. under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq)was added dropwise. The resulting solution was stirred at −78° C. for 30min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g,8.23 mmol, 1.0 eq) in Et₂O (5 mL) was added dropwise. The resultingreddish mixture was stirred at −78° C. for 2 h. TMSCl (pretreated withEt₃N (TMSCl:Et₃N=10:1, v:v), 1.14 mL, 1.2 eq) was added dropwise. Thedry ice bath was removed, and the resulting slurry was stirred at roomtemperature for 2 h. The reaction was cooled to −78° C. and a solutionof benzyl magnesium chloride in THF (2.0 M, 8.4 m, 2 eq) was addeddropwise. The resulting mixture was slowly warmed up to room temperatureand stirred at room temperature overnight. (NHC5 (100 mL) was added. Themixture was stirred at room temperature for 30 min, extracted with Et₂O(2×), washed with 1N NaOH, H₂O and brine, dried over Na₂SO₄, filtered,and concentrated to dryness. The residue was purified by flash columnchromatography (silica gel, hexanes:ethyl acetate) to give1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine(1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M-NH₃+H); ¹H NMR (400MHz, CHLOROFORM-D) δ ppm 7.66 (dd, J=6.7, 2.3 Hz, 1H), 7.49-7.59 (m,1H), 7.45 (s, 1H), 7.18-7.30 (m, 6H), 6.74 (d, J=6.9 Hz, 2H), 3.57 (m,2H).

Procedure 2

1-(4-Fluoro-3-(trimfluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine(300 mg, 0.67 mmol) and cyclopentyl isocyanate (0.4 mL, 5.3 eq) werestirred in 1,4-dioxane (2 mL) at room temperature overnight. Thereaction mixture was concentrated, and purified by flash chromatography(silica gel, hexanes/EtOAc) to give the racemic mixture of1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea(250 mg, yield: 67%). The racemate (250 mg) was dissolved in 10%isopropanol in heptane, and was resolved by chiral prep HPLC using an ADcolumn (10% isopropanol heptane/0.1% DEA, isocratic) to give the fasteluting enantiomer 1 (110 mg) corresponding to(S)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea,(analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% D_(E) A,isocratic), retention time=4.85 min) and the slow eluting enantiomer 2(105 mg) corresponding to(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea,(analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA,isocratic), retention time=14.11 min) LCMS (10-90% MeOH in H₂O with 0.1%TFA in a 4-min run), retention time=4.33 min, 557.32 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 7.36-7.44 (m, 2H), 7.23-7.29 (m, 3H), 7.13-7.21 (m,4H), 6.68-6.74 (m, 2H), 4.84 (s, 1H), 4.40 (s, br, 1H), 3.84-3.95 (m,3H), 1.88-1.98 (m, 2H), 1.56-1.68 (m, 4H), 1.34 (d, J=6.36 Hz, 2H).

Example 2

(R)-4-Fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 3 Preparation of1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene

To a solution of 1-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was addedpotassium tert-butoxide (76.6 g, 0.682 mole) at 0° C. The resultingmixture was stirred at room temperature for 3 h and quench with 4N HClslowly to pH≦1. The desired product was extracted with Et₂O (12 L) untilno product was detected in the aqueous layer. The Et₂O was evaporatedunder reduced pressure to one third the amount of the solvent and washedwith 1N NaOH (12 L). Then, the NaOH solution was adjusted to pH=3 andextracted with Et₂O until no desired product was detected in the aqueouslayer. The Et₂O was evaporated under reduced pressure and passed throughan Al₂O₃ column eluted with Et₂O to afford 3-bromo-5-fluorophenol as acolorless oil (48 g, 94% yield). LC-MS 190.33 (M+H); AnalyticalHPLC=2.26 minutes (0-100% CH₃CN in H₂O with 0.1% TFA in a 4-min run); ¹HNMR (400 MHz, CD₃OD) δ ppm 6.88-6.64 (m, 2H), 6.58-6.30 (m, 1H), 4.99(s, 1H).

To a solution of 3-bromo-5-fluorophenol (47 g, 0.249 mole) and2,2,3,3-tetrafluoroethyliodine (68 g, 0.298 mole) in DMSO (260 mL) wasadded potassium carbonate (137 g, 0.992 mole). The resulting mixture wasstirred at 70° C. for 16 h. The inorganic salt was removed by filtrationand the filter cake was washed with Et₂O (500 mL). The filtrate wasdiluted with 500 mL of H₂O and extracted with excess Et₂O (1.5 L). TheEt₂O layer was washed with 0.5 N NaOH (250 mL), H₂O, brine, and driedover Na₂SO₄. The solvent was evaporated under reduced pressure and thecrude product was passed through an Al₂O₃ column using Et₂O as theeluting solvent to afford1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (63 g, yield: 87%)as yellowish oil. LC-MS (ESI): 290.21 (M+H), retention time=3.66 minutes(0-100% MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz,CD₃OD) δ ppm 7.45-7.22 (m, 2H), 7.10 (d, J=9.23 Hz, 1H), 6.59-5.94 (m,1H).

Procedure 4(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanone

To an oven-dried round-bottomed flask cooled at −78° C., was added1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (7.20 g, 24.82mmol) in anhydrous ether (300 mL) under Argon, and the mixture wasstirred at −78° C. for 10 min. n-BuLi (2.5 M in hexanes, 11.5 mL, 28.75mmol, 1.16 eq) was added dropwise at −78° C. The reaction mixture wasstirred at −78° C. for 45 min. An Et₂O solution (20 mL) of4-fluorobenzonitrile (3.06 g, 25.29 mmol, 1.02 eq) was added dropwise.The resulting reddish solution was stirred at −78° C. for 2 h. Thereaction mixture was quenched by adding 1N HCl (200 mL), and the dryice-acetone bath was removed. The resulting slurry was stirred at roomtemperature for 1 h followed by the addition of Et₂O (100 mL). Theorganic layer was separated, and then washed with sat'd NaHCO₃, H₂O,brine, dried over MgSO₄, filtered, and concentrated to dryness. Theresidue was purified by flash chromatography (EtOAc/hexanes=0 to 30%) togive(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanoneas slightly tan oil (7.20 g, yield: 86.9%). ¹H NMR (400 MHz, CDCl₃) δppm 7.85-7.80 (m, 2H), 7.40-7.37 (m, 2H), 7.20-7.14 (m, 3H), 5.92 (tt,J=52, 2.8 Hz, 1H); LC-MS (ESI) 335.31 (M+H), retention time=3.81 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run).

Procedure 5(R,E/Z)-N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide

(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanone(3.3 g, 9.88 mmol) was stirred in anhydrous THF (20 mL) at r.t. underN₂. (R)-(+)-2-Methylpropane-2-sulfinamide (1.21 g, 10 mmol, 1.01 eq) wasadded as one single portion, followed by addition of Ti(OEt)₄ (3.09 mL,14.91 mmol, 1.51 eq). The resulting solution was heated at reflux for 48hours. The cooled mixture was evaporated. H₂O (100 mL) was added,followed by the addition of EtOAc (100 mL). The mixture was filteredthrough celite, and washed with EtOAc (200 mL). The filtrate was washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated todryness. The residue was purified by silica gel flash chromatography andwas eluted with hexanes and EtOAc (0-30% EtOAc in hexanes) to give(R)-N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamideas yellowish viscous oil which solidified after drying under vacuum aslight yellow solids (3.50 g, yield: 81.0%). LC-MS ESI 437.88 (M+H),retention time=3.83 min (10-90% MeOH in H₂O with 0.1% TFA in a 4-mingradient); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82-6.99 (br, m, 7H), 5.90(tt, J=52, 4 Hz, 1H), 1.31 (s, 9H).

Procedure 6

(R)-N-((3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide(150 mg, 0.34 mmol) was stirred in anhydrous CH₂Cl₂ (7 mL) at −78° C.for 5 min under Argon. BF₃Et₂O (0.10 mL, 2.0 eq) was added dropwise. Themixture was stirred at −78° C. for 10 min. Benzylmagnesium chloride (1.0M in Et₂O, 1.4 mL, 3.0 eq) was added slowly at −78° C., and theresulting mixture was stirred at −78° C. for 1.5 h. The reaction mixturewas quenched with sat. NH₄Cl and then extracted with Et₂O (2×). Thecombined organic portion was washed with H₂O and brine, dried overNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash chromatography (silica gel, EtOAc/hexanes=0-30%) to give thefast eluting fraction corresponding to(R)-N-((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(29 mg): ¹H NMR (400 MHz, CDCl₃) δ ppm 1.23 (s, 9H) 3.63 (d, J=12.4 Hz,1H), 3.94 (d, J=12.4 Hz, 1H), 4.21 (s, 1H), 6.90 (m, 1H), 5.90 (m, 1H),6.94-7.09 (m, 4H), 7.16-7.20 (m, 4H), 7.31-7.39 (m, 2H); LC-MS (ESI)530.36 (M+H), retention time=4.11 min (10-90% MeOH in H₂O with 0.1% TFAin a 4-min run); and the slow eluting fraction corresponding to(R)-N-((R)-1-(3-fluoro-5-(,1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(146 mg, total yield: 96.4%): ¹H NMR (400 MHz, CDCl₃) δ ppm 7.35-7.43(m, 2H), 7.13-7.20 (m, 3H), 7.07 (t, J=8.72 Hz, 2H), 6.93 (dd, J=7.58,1.77 Hz, 2H), 6.84 (d, J=8.59 Hz, 1H), 6.70 (m, 2H), 5.85 (tt, J=52, 4Hz, 1H), 4.25 (s, 1H), 4.02 (d, J=12.63 Hz, 1H), 3.58 (d, J=12.63 Hz,1H), 1.20 (s, 9H); ¹³C NMR (CDCl₃) δ ppm 23.02, 46.99, 56.53, 65.70,104.55, 104.96, 105.37, 107.06, 107.47, 107.92, 108.17, 109.56, 109.97,112.32, 112.55, 115.37, 115.58, 116.13, 116.41, 116.69, 119.12, 127.21,128.14, 130.91, 130.99, 132.07, 134.34, 137.48, 137.51, 149.09, 149.21,150.52, 150.45, 161.20, 163.67; LC-MS (ESI) 530.36 (M+H), retentiontime=4.11 min (10-90% MeOH in H₂O with 0.1% TFA in a 4-min run).

(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine

(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(234 mg, 0.442 mmol) was stirred in 4N HCl in dioxane (1.5 mL) and MeOH(1.5 mL) at room temperature under Ar for 10 min. The reaction mixturewas concentrated, and then purified by flash chromatography (silica gel,hexanes/EtOAc) to give(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(169 mg, 90%). LC-MS (ESI) 409.16 (M-NH₃+H), retention time=3.26 minutes(0-100% MeOH in H₂O with 0.1% TFA in 4-min run); Analytical HPLC: 2.52minutes (0-100% CH₃CN in H₂O with 0.1% TFA in 4-min run); ¹H NMR (400MHz, CD₃OD) δ ppm 7.29-7.50 (m, 2H), 6.87-7.22 (m, 8H), 6.77 (d, J=6.15Hz, 2H), 6.04-6.48 (m, 1H), 3.57 (s, 2H).

Procedure 7(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide

To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(30 mg, 0.079 mmol) in CH₂Cl₂ (0.2 mL) was added4-fluoro-3-(trifluoromethyl)benzoyl chloride (0.048 mL, 0.158 mmol),followed by Et₃N (0.04 mL, 0.158 mmol). The resulting mixture wasstirred at room temperature for 5 h. The crude product was purified on apreparative HPLC column type using 30 to 100% CH₃CN in H₂O with 0.1% TFAfor 10 minutes as mobile phase. The solvent was removed under reducedpressure to afford(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(35 mg, 80% yield) as white powder. LC-MS (ESI) 568.30 (M+H), retentiontime=4.27 min (0-100% MeOH in H₂O with 0.1% TFA in a 4-min run);Analytical HPLC: 3.95 min (0-100% CH₃CN in H₂O with 0.1% TFA in a 4-minrun, purity 100%); ¹H NMR (400 MHz, CD₃OD) δ ppm 3.88-4.01 (m, 1H), 4.10(d, J=13.18 Hz, 1H), 6.69 (d, J=7.47 Hz, 2H), 6.97-7.51 (m, 11H), 7.99(d, J=5.71 Hz, 2H), 8.90 (s, 1H).

Example 3

(R)-1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)propan-2-olProcedure 8

(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanaminewas prepared as described in Procedures 4, 5 and 6.(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(50 mg, 0.133 mmol) was dissolved in anhydrous acetonitrile (0.26 mL).(R)-2-(trifluoromethyl)oxirane (0.07 mL, 0.625 mmol), (approximate 85:15ratio of R to S) was added to the solution in a microwave vial followedby Yb(OSO₂CF₃)₃ (0.005 g, 0.008 mmol). The sealed vial was heated to160° C. for 30 minutes under microwave irradiation. The crude productwas purified by preparative HPLC using 30-100% acetonitrile in H₂O with0.1% TFA as mobile phase to give(R)-1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)propan-2-olas a colorless oil (30 mg, 46% yield). LC-MS (ESI): 361.15 (M+H),retention time=4.10 min (0-100% MeOH in H₂O with 0.1% TFA); AnalyticalHPLC: 3.49 min (CH₃CN in H₂O with 0.1% TFA in 4 min run, purity 100%);¹H NMR (400 MHz, CD₃OD) δ ppm 2.59-2.73 (m, 1H), 2.72-2.84 (m, 1H), 3.69(m, 2H), 4.09 (m, 1H), 6.61-6.82 (m, 2H), 7.00-7.19 (m, 5H), 7.20-7.48(m, 5H).

Example 4

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(3,3,3-trifluoropropyl)ureaProcedure 9

(R)-1-cyclopentyl-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureawas prepared as described in Procedure 2. To a microwave vial containing(R)-1-cyclopentyl-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(20 mg, 0.037 mmol) was added a pre-mixed solution of3,3,3-trifluoromethylpropylamine (25 mg, 0.224 mmol) and Et₃N (0.03 mL,0.224 mmol) in THF (0.025 mL). The sealed vial was subjected tomicrowave irradiation at 150° C. for 1500 sec followed by dilution withMeOH. The crude product was isolated by preparative HPLC column typeusing 30-100% acetonitrile in H₂O with 0.1% TFA as mobile phase toafford(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(3,3,3-trifluoropropyl)urea(76%) as white powder. LCMS (ESI): 565.36 (M+H), retention time=3.96 min(0-100% MeOH in H₂O in a 4-min run); ¹H NMR (400 MHz, CD₃OD) δ ppm2.18-2.41 (m, 2H), 3.34 (m, 2H), 3.75-3.87 (m, 1H), 3.88-4.00 (m, 1H),6.07-6.45 (m, 1H), 6.71 (d, J=7.03 Hz, 2H), 6.85-7.05 (m, 5H), 7.05-7.22(m, 5H).

Example 5

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(thiazol-2-yl)ureaProcedure 10

(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(48 mg, 0.11 mmol) was stirred in THF (0.5 mL) and H₂O (0.05 mL) at roomtemperature. K₂CO₃ (100 mg, 0.72 mmol, 6.6 eq) was added followed by theaddition of isopropenyl chloroformate (0.030 mL, 0.275 mmol, 2.5 eq).The reaction mixture was stirred at room temperature overnight. Themixture was filtered, and the filtrate concentrated to dryness to givecrude (R)-prop-1-en-2-yl1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamateas colorless film (60 mg, yield: quantative). LCMS: 4.18 min 409.27(M-COOisopropenyl-NH₃+H) (4 min gradient, MeOH/H₂O 0.1% TFA).

(R)-prop-1-en-2-yl1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamate(15 mg, 0.029 mmol) and 2-aminothiazole (8.2 mg, 0.082 mmol, 2.8 eq),and N-methylpyrrolidine (0.9 μl, 0.3 eq) were stirred in THF (0.3 mL) ina microwave vial. The reaction mixture was heated at 150° C. for 20 minunder microwave irradiation. After cooling, the solvent was evaporated.The residue was purified by reverse phase HPLC (20-90% CH₃CN in H₂O with0.1% TFA) to give pure(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(thiazol-2-yl)ureaas white solids (6.5 mg, yield: 40.6%). ¹H NMR (400 MHz, CDCl₃-D) δ ppm7.29 (In, 1H), 7.23-7.18 (m, 3H), 7.16 (t, J=8.0 Hz, 2H), 7.02 (t, J=8.5Hz, 2H), 6.94-6.89 (m, 4H), 6.71 (d, J=6.82 Hz, 2H), 5.86 (tt, J=47.1,2.9 Hz, 1H), 3.84-3.75 (m, 2H); LC-MS (ESI) 552.28 (M+H), retentiontime=4.12 min (10-90% MeOH in H₂O with 0.1% TFA in a 4-min run).

TABLE 1 Retention Time Min./ Ex. Molecular Prepared in the manner No.Structure Name Mass described in: 6

l-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-l-(4-fluorophenyl)-2- phenylethyl)urea 3.61 LC 489.34 [M + H]⁺ Procedure1 and 2 7

1-cyclopentyl-3-(1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.30 LC557.3 [M + H]⁺ Procedure 1 and 2 8

l-cyclopentyl-3-(1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.30 LC557.3 [M + H]⁺ Procedure 1 and 2 9

(S)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)urea 3.60 LC 489.33 [M + H]⁺ Procedure4, 5, 6 and 2 10

(R)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)urea 3.61 LC 489.33 [M + H]⁺ Procedure4, 5, 6 and 2 11

1-(1,1-bis(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenylethyl)-3-cyclopentylurea 3.87 LC 557.34 [M + H]⁺ Procedure 14 and 2 12

(R)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-2-phenyl-1-(3- (trifluoro- methyl)phenyl)ethyl)urea 4.30 LC 539.38 [M +H]⁺ Procedure 4, 5, 6 and 2 13

(R)-1-cyclopentyl-3-(1- (3,4-difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)urea 3.64 LC 507.34 [M + H]⁺Procedure 4, 5, 6 and 2 14

(S)-1-cyclopentyl-3-(1- (3,4-difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)urea 3.64 LC 507.14 [M + H]⁺Procedure 4, 5, 6 and 2 15

2-(4-(3-(1-(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenyl-1-(3-(trifluoromethyl)phenyl)eth- yl)ureido)piperidin-1- yl)acetic acid 3.75LC 612.4 [M + H]⁺ Procedure 1 and 2 16

1-(1-(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenyl-1-(3-(trifluoromethyl)phenyl)eth- yl)-3-(1-(2- hydroxyethyl)piperidin-4-yl)urea 3.72 LC 598.45 [M + H]⁺ Procedure 1 and 2 17

(R)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-methoxy-3- (trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.22 LC569.39 [M + H]⁺ Procedure 4, 5, 6 and 2 18

(R)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-methyl-3- (trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.42 LC553.38 [M + H]⁺ Procedure 4, 5, 6 and 2 19

1-cyclopentyl-3-(2- phcnyl-1,1-bis(3-(1,1,2,2- tetrafluoro-ethoxy)phenyl)ethyl)urea 4.13 LC 617.4 [M + H]⁺ Procedure 1 and 2 20

(R)-1-cyclopentyl-3-(1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2- tetrafluoroethoxy)phenyl)- 2-phenylethyl)urea3.74 LC 605.37 [M + H]⁺ Procedure 1, 3 and 2 21

(R)-1-cyclopentyl-3-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.17 LC 519.37 [M + H]⁺Procedure 4, 5, 6 and 2 22

(R)-1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-2-phenyl-1-(3- (trifluoro- methoxy)phenyl)ethyl)urea 4.30 LC 555.40 [M +H]⁺ Procedure 4, 5, 6 and 2 23

(R)-1-cyclobutyl-3-(1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2- tctrafluoroethoxy)phenyl)- 2-phenylethyl)urea3.64 LC 591.39 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 24

(R)-1-(1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3-(2- methylpyridin-4-yl)urea2.64 LC 648.49 [M + Na]⁺ Procedure 3, 4, 5, 6 and 9 25

1-((R)-1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3-(2-oxo-tetrahydrofuran-3-yl)urea 3.30 LC 621.39 [M + H]⁺ Procedure 3, 4, 5, 6and 9 26

(R)-1-(1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3-(3,3,3- trifluoropropyl)urea3.59 LC 633.32 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 27

(R)-1-(1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3- isopropylurea 3.62 LC579.34 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 28

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-methoxyphenyl)-2- phenylethyl)urea 4.13 LC 501.3 [M + H]⁺ Procedure1 and 2 29

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-(methylthio)phenyl)- 2-phenylethyl)urea 4.24 LC 517.26 [M + H]⁺Procedure 1 and 2 30

l-cyclopentyl-3-(1-(4- (difluoromethoxy)phenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.12 LC 537.27 [M + H]⁺Procedure 1 and 2 31

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)- 2-phenyl-1-p-tolylethyl)urea 4.24 LC 485.32 [M + H]⁺ Procedure 1 and 2 32

1-(1-(4-chloro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)-3- cyclopentylurea 4.30 LC573.23 [M + H]⁺ Procedure 1 and 2 33

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-phenoxyphenyl)-2- phenylethyl)urea 4.38 LC 563.32 [M + H]⁺Procedure 1 and 2 34

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(3-methoxyphenyl)-2- phenylethyl)urea 4.14 LC 501.32 [M + H]⁺Procedure 1 and 2 35

1-cyclopentyl-3-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(2-fluorophenyl)-2- phenylethyl)urea 4.12 LC 489.26 [M + H]⁺ Procedure1 and 2 36

1-cyclopentyl-3-(1-(2- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5- (trifluoromethyl)phenyl)- 2-phenylethyl)urea 4.17 LC557.26 [M + H]⁺ Procedure 1 and 2 37

1-(1-(4-tert-butylphenyl)- 1-(3-fluoro-5- (trifluoromethyl)phenyl)-2-phenylethyl)-3- cyclopentylurea 4.47 LC 527.33 [M + H]⁺ Procedure 1and 2 38

(R)-1-(1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3-(2,2,2- trifluoroethyl)urea3.32 LC 619.31 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 39

(R)-1-(1-(3-fluoro-5- (1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3-(2,2,2- trifluoroethyl)urea 3.14 LC551.21 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 40

(R)-1-(1-(3-fluoro-5- (trifluoromethyl)phenyl)- 1-(4-methyl-3-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(3,3,3- trifluoropropyl)urea4.37 LC 580.98 [M + H]⁺ Procedure 4, 5, 6 and 2 41

(R)-1-(1-(3-fluoro-5- (trifluoromethyl)phenyl)- 1-(4-methyl-3-(trifluoromethyl)phenyl)- 2-phenylethyl)-3- isopropylurea 4.36 LC 527.08[M + H]⁺ Procedure 4, 5, 6 and 2 42

(R)-1-(1-(3-fluoro-5- (trifluoromethyl)phenyl)- 1-(4-methyl-3-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(2,2,2- trifluoroethyl)urea4.32 LC 567.04 [M + H]⁺ Procedure 4, 5, 6 and 2 43

1-((R)-1-(3-fluoro-5- (trifluoromethyl)phenyl)- 1-(4-methyl-3-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(1- hydroxy-4-methylpentan-2-yl)urea 4.40 LC 585.13 [M + H]⁺ Procedure 4, 5, 6 and 2 44

1-((R)-1-(3-fluoro-5- (trifluoromethyl)phenyl)- 1-(4-methyl-3-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(1- hydroxy-4-methylpentan-2-yl)urea 4.41 LC 585.13 [M + H]⁺ Procedure 4, 5, 6 and 2 45

(R)-1-(1-(3-fluoro-5- (1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3- isopropylurea 3.95 LC 511.39 [M +H]⁺ Procedure 3 4, 5, 6 and 9 46

(R)-1,1-dicyclopropyl-3- (1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 1-(4-fluorophenyl)-2- phenylethyl)urea 4.12LC 549.32 [M + H]⁺ Procedure 3 4, 5, 6 and 9 47

(1S)-2-(3-((R)-1-(3- fluoro-5-(1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)ureido)cyclo- pentanecarboxylic acid3.93 LC 581.04 [M + H]⁺ Procedure 3, 4, 5, 6 and 9 48

(S)-1-(1-(3-chloro-4- fluorophenyl)-1-(3-fluoro- 5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3- cyclopentylurea 3.72 LC571.36 [M + H]⁺ Procedure 3, 4, 5, 6 and 2 49

1-((R)-3,3- difluorocyclopentyl)-3- ((R)-1-(4-fluoro-3-(trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)urea 4.17 LC 641.3 [M + H]⁺Procedure 3, 4, 5, 6 and 12 50

(R)-1-(1-(4-fluoro-3- methoxyphenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(2,2,2- trifluoroethyl)urea3.94 LC 532.98 [M + H]⁺ Procedure 4, 5, 6 and 9 51

(R)-3-(1-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-1-(2- hydroxyethyl)-1-isopropylurea 4.09 LC 623.02 [M + H]⁺ Procedure 4, 5, 6 and 9 52

(R)-1-(1-(4-fluoro-3- methoxyphenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethyl)-3-(3,3,3- trifluoropropyl)urea3.49 LC 547.00 [M + H]⁺ Procedure 4, 5, 6 and 9 53

(S)-1-(1-(3,5- bis(trifluoromethyl) phenyl)-1-(4- fluorophenyl)-2-phenylethyl)-3- cyclopentylurea 3.82 LC 539.03 [M + H]⁺ Procedure 4, 5,6 and 2 54

(R)-1-(1-(3,5- bis(trifluoromethyl) phenyl)-1-(4- fluorophenyl)-2-phenylethyl)-3- cyclopentylurea 3.80 LC 539.03 [M + H]⁺ Procedure 4, 5,6 and 2 55

(R)-1-(1-(3-fluoro-5- (1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3-(3,3,3- trifluoropropyl)urea 3.96LC 565.36 [M + H]⁺ Procedure 3, 4, 5, 6 and 9

TABLE 2 Retention Time Min./ Ex. Molecular Prepared in the manner No.Structure Name Mass described in: 56

(R)-4-fluoro-N-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide 3.95 LC568.30 [M + H]⁺ Procedure 4, 5, 6 and 7 57

(S)-4-fluoro-N-(1-(3- fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide 3.95 LC568.24 [M + H]⁺ Procedure 4, 5, 6 and 7 58

N-(1,1-bis(3-fluoro-5- (trifluoromethyl)phenyl)-2- phenylethyl)-4-fluorobenzamide 3.83 LC 568.3 [M + H]⁺ Procedure 1 and 7 59

(S)-N-(1-(3,4- difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide 3.95 LC 586.26 [M + H]⁺ Procedure 4, 5, 6 and7 60

(R)-N-(1-(3,4- difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide 3.93 LC 497.3 [M + H]⁺ Procedure 4, 5, 6 and7 61

(R)-4-fluoro-N-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-3- methylbenzamide 3.79 LC544.35 [M + H]⁺ Procedure 4, 5, 6 and 7 62

(R)-3,4-difluoro-N-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)benzamide 3.73 LC 570.32 [M +Na]⁺ Procedure 4, 5, 6 and 7 63

(R)-3-fluoro-N-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)benzamide 3.67 LC 530.33 [M +H]⁺ Procedure 4, 5, 6 and 7 64

(R)-3,5-difluoro-N-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)benzamide 3.75 LC 548.33 [M +H]⁺ Procedure 4, 5, 6 and 7 65

(R)-N-(1-(4-fluoro-3- methoxyphenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide3.86 LC 580.36 [M + H]⁺ Procedure 4, 5, 6 and 7 66

(R)-4-fluoro-N-(1-(4- fluoro-3-methoxyphenyl)- 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide3.90 LC 598.36 [M + H]⁺ Procedure 4, 5, 6 and 7 67

(R)-N-(1-(4-fluoro-3- methoxyphenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-6- (trifluoromethyl)nicotinamide 3.70 LC 581.34 [M + H]⁺ Procedure 4, 5, 6 and 7 68

(R)-4-fluoro-N-(1-(3- fluoro-5-(1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide 3.95 LC616.17 [M + H]⁺ Procedure 4, 5, 6 and 7 69

(R)-N-(1-(3-fluoro-5- (1,1,2,2- tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide 3.83 LC598.37 [M + H]⁺ Procedure 4, 5, 6 and 7 70

(R)-N-(1-(3-fluoro-5- (trifluoromethyl)phenyl)-1- (4-fluorophenyl)-2-phenylethyl)-3- (trifluoromethyl)benzamide 3.89 LC 550.36 [M + H]⁺Procedure 4, 5, 6 and 7 71

(S)-N-(1-(3-chloro-4- fluorophenyl)-1-(3-fluoro- 5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3- (trifluoromethyl)benzamide3.95 LC 632.32 [M + H]⁺ Procedure 4, 5, 6 and 7 72

(S)-N-(1-(2,4- difluorophenyl)-1-(3- fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-3- (trifluoromethyl)benzamide3.86 LC 616.34 [M + H]⁺ Procedure 4, 5, 6 and 7 73

(R)-N-(1-(3-fluoro-5- (1,1,2,2- tetrafluoroethoxy)phenyl)-1-(3-fluorophenyl)-2- phenylethyl)-3- (trifluoromethyl)benzamide 3.81 LCN. Observed [M + H]⁺ Procedure 4, 5, 6 and 7 74

(S)-N-(1-(3-chloro-4- fluorophenyl)-1-(3-fluoro- 5-(1,1,2,2-tetrafluoroethoxy)phenyl)- 2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide 4.03 LC 650.08 [M + H]⁺ Procedure 4, 5, 6 and7

TABLE 3 Retention Time Min./ Ex. Molecular Prepared in the manner No.Structure Name Mass described in: 75

(R)-1-chloro-3-((R)-1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2- tetrafluoroethoxy)phenyl)- 2-phenylethylamino)propan-2-ol 3.24 LC 586.43 [M + H]⁺ Procedure 3, 4, 5, 6 and 8 76

(S)-1-chloro-3-((R)-1-(4- fluoro-3- (trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2- tetrafluoroethoxy)phenyl)- 2-phenylethylamino)propan-2-ol 3.24 LC 586.43 [M + H]⁺ Procedure 3, 4, 5, 6 and 8 77

(R)-1,1,1-trifluoro-3-((R)- 1-(3-fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethylamino)propan- 2-ol 3.83 LC No obs [M +H]⁺ Procedure 4, 5, 6 and 8 78

(R)-1,1,1-trifluoro-3-((S)- 1-(3-fluoro-5- (trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2- phenylethylamino)propan- 2-ol 3.48 LC No obs [M +H]⁺ Procedure 4, 5, 6 and 8 79

(R)-3-(1,1-bis(3-fluoro-5- (trifluoromethyl)phenyl)-2-phenylethylamino)- 1,1,1-trifluoropropan-2-ol 3.88 LC No obs. [M + H]⁺Procedure 4, 5, 6 and 8 80

(R)-3-((R)-1-(3,4- difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethylamino)-1,1,1-trifluoropropan-2-ol 3.63 LC No obs. [M + H]⁺ Procedure 4, 5, 6and 8 81

(R)-3-((S)-1-(3,4- difluorophenyl)-1-(3- fluoro-5-(trifluoromethyl)phenyl)- 2-phenylethylamino)-1,1,1-trifluoropropan-2-ol 3.64 LC No obs. [M + H]⁺ Procedure 4, 5, 6and 8

Additional compounds of the present invention were prepared byprocedures analogous to those described above and to the additionalprocedures described below.

Example 82

1-(1,1-bis(3-(trifluoromethoxy)phenyl)but-3-enyl)-3-cyclopentylureaProcedure 11 Bis(3-(trifluoromethoxy)phenyl)methanone

Using the same procedure as described in Example 2, Procedure 4,bis(3-(trifluoromethoxy)phenyl)methanone was obtained. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.39-7.45 (m, 1H),) 7.36 (m, 1H), 7.25 (d, J=15.92 Hz, 1H),7.15-7.20 (m, 1H); ¹³C NMR (CDCl₃) δ ppm 193.27, 149.29, 138.66, 130.10,128.27, 125.23, 124.26, 122.26, 121.69, 119.13, 116.56; LC-MS (ESI)351.2 (M+H), retention time=4.0 min (10-90% MeOH in H₂O with 0.1% TFA ina 4-min run).

(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide

Using the same procedure as that of Procedure 5,(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamidewas obtained. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62-7.28 (br, m, 8H),) 1.34(s, 9H); LC-MS (ESI) 454.28 (M+H), retention time=4.12 min (10-90% MeOHin H₂O with 0.1% TFA in a 4-min run).

1-(1,1-bis(3-(trifluoromethoxy)phenyl)but-3-enyl)-3-cyclopentylurea

Using similar procedures as Procedure 6, and2,1-(1,1-bis(3-(trifluoromethoxy)phenyl)but-3-enyl)-3-cyclopentylureawas obtained. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.41 (t, J=7.96 Hz, 2H),7.37-7.31 (m, 2H) 7.27 (m, 2H), 7.18 (d, J=8.08 Hz, 2H), 5.48-5.36 (m,1H), 5.25-5.15 (m, 3H), 4.10 (s, br, 1H), 3.86-3.96 (m, 1H), 3.17 (d,J=6.82 Hz, 2H), 1.86-1.76 (m, 2H), 1.53-1.42, (m, 4H) 1.18-1.07 (m, 2H);LC-MS (ESI) 503.33 (M+H), retention time=4.26 min (10-90% MeOH in H₂Owith 0.1% TFA in a 4-min run).

Example 83

(R)-1-(3,3-difluorocyclopentyl)-3-(2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureaProcedure 12

To the solution of 3-oxocyclopentanecarboxylic acid (2.85 g, 22.2 mmol)in dry CH₂Cl₂ (4 mL) was added oxalyl chloride (2.0M in dichloromethane,13 mL) at 0° C. over 15 min followed by DMF (50 mL) After the additionwas complete, the reaction mixture was stirred for 2 h (0° C. to rt).Tetrabutylammonium bromide (35 mg) was then added followed by a solutionof sodium azide (2.17 g, 26.7 mmol, in the minimum amount of H₂O, 9 mL)at 0° C., and the resulting light brown reaction mixture was stirred for1 h at rt. The reaction was monitored and upon completion, the organicphase was separated. The aqueous phase was extracted with CH₂Cl₂ (3×8mL). The combined organic phases were washed with brine, dried withsodium sulfate, and filtered through a 2 cm plug of silica. The silicagel plug was washed with CH₂Cl₂, twice followed with 10% EtOAc inCH₂Cl₂. The resulting pale yellow filtrate was partially concentrated.Benzyl alcohol (25 mL) was added and the remainder of CH₂Cl₂ was removedunder vacuum. The light brown solution was heated at 100° C. for 3 h.After it was cooled to room temperature, the brown solution was vacuumdistilled. Benzyl alcohol was collected and the viscous brown oilresidue was purified by flash chromatography (120 g SiO₂, 0-40%EtOAc/hexane) to provide benzyl 3-oxocyclopentylcarbamate as a paleyellow and colorless oil (2.39 g, 46% yield). ¹H NMR (CDCl₃, 400 MHz):7.35 (m, 5H), 5.09 (s, 2H), 4.87 (br, 1H), 4.28 (m, 1H), 2.63 (m, 1H),2.39-2.15 (m, 4H), 1.86 (m, 1H). ¹³C NMR (CDCl₃, 400 MHz): 215.7, 155.8,136.2, 128.6, 128.3, 128.2, 66.9, 49.3, 45.2, 37.0, 29.9. LC/MS:[M+H]=234.1.

To a solution of benzyl 3-oxocyclopentylcarbamate (2.32 g, 9.96 mmol) inCH₂Cl₂ (10 mL) was added DAST (4.3 mL, 28.9 mmol) at rt. The reactionmixture turned brown while shaken at rt overnight. When thetransformation was complete by HPLC, brine was added at 0° C. slowly toquench the reaction [Caution: reacted violently]. CH₂Cl₂ was added andthe solution was extracted with CH₂Cl₂ (3×10 mL). The combined organicphases were dried over Na₂SO₄, and concentrated. The residue waspurified by flash chromatography (40 g SiO₂, 0-40% EtOAc/hexane) tofurnish benzyl 3,3-difluorocyclopentylcarbamate as an off-white solid(1.5 g, 59%). ¹H NMR (CDCl₃, 400 MHz): 7.35 (m, 5H), 5.09 (s, 2H), 4.90(br, 1H), 4.23 (m, 1H), 2.50 (m, 1H), 2.25-1.98 (m, 4H), 1.70 (m, 1H).¹³C NMR (CDCl₃, 400 MHz): 155.6, 136.2, 128.6, 128.3, 128.2, 66.9,50.86, 49.3, 42.6 (t), 34.2 (t), 30.6. ¹⁹F NMR (CDCl₃, with CFCl₃ asstandard, 400 MHz): −88.2 (m, 1F), −91.4 (m, 1F).

Benzyl 3,3-difluorocyclopentylcarbamate (1.5 g, 5.88 mmol) in 6N HCl (6mL) was heated at 100° C. for 20 h. After the reaction mixture wascooled to rt, the brown solution was extracted with Et₂O (2×2 mL) toremove unreacted starting material and toluene. The aqueous phase wasdried in the speed vac with heating to give 3,3-difluorocyclopentanaminehydrochloride as a light brown solid (0.79 g, 85% yield). ¹H NMR(MeOD-d₄, 400 MHz): 4.79 (m, 1H), 2.62 (m, 1H), 2.32 (m, 2H), 2.18 (m,2H), 1.87 (m, 1H). ¹³C NMR (MeOD-d₄, 400 MHz): 131.4 (t), 41.0 (t), 34.8(t), 28.9. ¹⁹F NMR (MeOD-d₄, with CFCl₃ as standard, 400 MHz): −93.0 (m,2F). LC/MS: [M+H]=121.9.

2-Phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine was preparedaccording as described for Procedure 6. To a solution of2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (77 mg, 0.17mmol) in CH₂Cl₂ (1 mL), was added K₂CO₃ (241 mg, 1.7 mmol) followed by4-nitrophenyl chloroformate (70 mg, 0.35 mmol). The reaction mixture wasstirred at rt until the starting material was consumed. The solution wasdiluted with CH₂Cl₂ and washed with NaHCO₃. The organic layer wereseparated and the aqueous layer was extracted with CH₂Cl₂ (3×). Thecombined organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was taken up in anhydrous CH₂Cl₂(1.6 mL) and this mixture was used as a stock solution of theintermediate carbamate (0.11 M in CH₂Cl₂).

4-Nitrophenyl 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate(400 μL of the above stock solution, 0.044 mmol) was added to a vialfollowed by 3,3-difluorocyclopentanamine hydrochloride (14 mg, 0.087mmol, 66.4% ee R) and Hunig's base (15 μL, 0.087 mmol). The reaction wasmonitored for the disappearance of the carbamate. Upon completion, thereaction mixture was diluted with CH₂Cl₂, washed with successively withNaHCO₃ and 1N NaOH, and extracted with CH₂Cl₂ (3×). The combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification of the residue was accomplished by preparativeHPLC (YMC Combiprep ODS-A 30×50 mm; mobile phase: 10% MeOH/90% H₂O/0.1%TFA) to provide the desired urea (9.1 mg) as a film. ¹H NMR (500 MHz,CDCl₃, diastereomeric mixture, ca. 83:17) δ 7.36 (t, J=7.5 Hz, 2H),7.22-7.10 (m, 7H), 7.06 (s, 2H), 6.65 (d, J=5.0 Hz, 2H), 4.89 (s, 1H),4.33-4.24 (m, 1H), 4.23-4.14 (m, 1H), 3.76 (s, 2H), 2.42-2.30 (m, 1H),2.13-1.93 (m, 3H), 1.77-1.67 (m, 1H), 1.48-1.41 (m, 1H); LC/MS(MeOH/H₂O/NH₄OAc mobile phase) rt=4.26 min; [M+H]=589.3.

Example 84

(R)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamineProcedure 13

(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(21.5 mg, 0.057 mmol) in dichloroethane (0.5 mL) in a two drum vial wasadded 4-fluoro-3-(trifluoromethyl)benzaldehyde (21.9 mg, 0.114 mmol)followed by a drop of acetic acid. The reaction mixture was shaken for20 minutes at room temperature before NaBH(OAc)₃ (36.3 mg, 0.171 mmol)was added. The reaction was stirred at room temperature overnight. Thesolvents were removed and the residue was purified by preparative HPLC(phenominex C18 column, 21×100 mm, 5μ) using MeOH/H₂O (with 0.1% TFA) togive(R)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamineas a colorless oil (17.5 mg, 46% yield). LCMS: 4.32 min (4 min gradient,MeOH/H₂O 0.1% TFA); ¹H NMR (400 MHz, CDCl₃) δ ppm 3.78-3.91 (m, 4H),6.60 (d, J=7.47 Hz, 2H), 7.14-7.27 (m, 7H), 7.35-7.48 (m, 6H).

TABLE 4 Retention Time Min./ Ex. Molecular Prepared in the manner No.Structure Name Mass described in: 85

1-(2,2,3,3,3- pentafluoropropyl)-3-(2- phenyl-1,1-bis(3-(trifluoromethoxy)phen- yl)ethyl)urea 4.30 LC 617.3 [M + H]⁺ Procedure11 and 12 86

1-cyclopentyl-3-(2-(2- methoxyphenyl)-1,1-bis(3- (trifluoromethoxy)phen-yl)ethyl)urea 3.92 LC 583.03 [M + H]⁺ Procedure 11 and 2

TABLE 5 Retention Time Min./ Prepared in the Ex. Molecular mannerdescribed No. Structure Name Mass in: 87

2-phenoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)propanamide 4.37 LC 590.16 [M + H]⁺ Procedure 11 and 7 88

2-phenyl-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)butanamide 4.39 LC 588.22 [M + H]⁺ Procedure 11 and 7 89

4-methyl-3-nitro-N-(2-phenyl- 1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.31 LC 605.15 [M + H]⁺ Procedure 11 and 7 90

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl) benzamide 4.24 LC546.14 [M + H]⁺ Procedure 11 and 7 91

2-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.27 LC 564.09 [M + H]⁺ Procedure 11 and 7 92

2-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.26 LC 560.14 [M + H]⁺ Procedure 11 and 7 93

3-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.36 LC 589.09 [M + H]⁺ Procedure 11 and 7 94

3-ethoxy-N-(2-phenyl-1,1- bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.32 LC 590.16 [M + H]⁺ Procedure 11 and 7 95

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide 4.36 LC 614.1 [M + H]⁺ Procedure 11 and 796

4-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.28 LC 564.12 [M + H]⁺ Procedure 11 and 7 97

4-methoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.26 LC 576.15 [M + H]⁺ Procedure 11 and 7 98

4-tert-butyl-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.51 LC 602.16 [M + H]⁺ Procedure 11 and 7 99

4-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethoxy)phenyl)ethyl)benzamide 4.30 LC 560.14 [M + H]⁺ Procedure 11 and 7 100

methyl 2-oxo-2-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethylamino)acetate 4.13 LC 528.08 [M + H]⁺ Procedure 11 and 7 101

ethyl 2-oxo-2-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethylamino)acetate 4.18 LC 542.14 [M + H]⁺ Procedure 11 and 7 102

2-methyl-1-oxo-1-(2-phenyl- 1,1-bis(3- (trifluoromethoxy)phenyl)ethylamino)propan-2-yl acetate 4.19 LC 570.15 [M + H]⁺ Procedure 11 and7 103

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl) isobutyramide4.22 LC 512.14 [M + H]⁺ Procedure 11 and 7 104

2-ethyl-N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)hexanamide 4.45 LC 568.21 [M + H]⁺ Procedure 11 and 7 105

methyl 4-oxo-4-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethylamino)butanoate 4.17 LC 556.13 [M + H]⁺ Procedure 11 and 7 106

ethyl 4-oxo-4-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethylamino)butanoate 4.21 LC 570.15 [M + H]⁺ Procedure 11 and 7 107

(1R,2R)-2-phenyl-N-(2-phenyl- 1,1-bis(3-(trifluoromethoxy) phenyl)ethyl)cyclopropanecarboxamide 4.37 LC 586.15 [M + H]⁺ Procedure 11 and 7 108

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)cyclobutanecarboxamide 4.27 LC 524.13 [M + H]⁺ Porcedure 11 and 7 109

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)cyclopentanecarboxamide 4.32 LC 538.14 [M + H]⁺ Procedure 11 and 7 110

3-cyclopentyl-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)propanamide 4.48 LC 566.17 [M + H]⁺ Procedure 11 and 7 111

2-(4-fluorophenyl)-N-(2- phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)acetamide 4.29 LC 578.1 [M + H]⁺ Procedure 11 and 7 112

2-chloro-5-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.27 LC 598.06 [M + H]⁺ Procedure 11 and 7 113

3-chloro-2-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.35 LC 598.04 [M + H]⁺ Procedure 11 and 7 114

4-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide 4.43 LC 628.11 [M + H]⁺ Procedure 11 and 7115

2-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)-5-(trifluoromethyl)benzamide 4.36 LC 648.05 [M + H]⁺ Procedure 11 and 7116

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)benzofuran-2-carboxamide 4.39 LC 586.12 [M + H]⁺ Procedure 11 and 7 117

4-phenoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethoxy)phenyl)ethyl)butanamide 4.39 LC 604.16 [M + H]⁺ Procedure 11 and 7 118

4-chloro-2-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)benzamide 4.39 LC 598.1 [M + H]⁺ Procedure 11 and 7 119

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)-2-o-tolylacetamide 4.35 LC 574.15 [M + H]⁺ Procedure 11 and 7 120

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethoxy)phenyl)ethyl)benzofuran-2-carboxamide 4.57 LC 600.14 [M + H]⁺ Procedure 11 and 7 121

2,5-difluoro-4-methyl-N-(2- phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl) benzamide 4.40 LC 596.1 [M + H]⁺Procedure 11 and 7 122

N-(2-phenyl-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)furan-2-carboxamide 4.19 LC 536.13 [M + H]⁺ Procedure 11 and 7 127

3-nitro-N-(2-phenyl-1,1-bis(3- (trilfuoromethyl)phenyl)ethyl) benzamide4.19 LC 559.22 [M + H]⁺ Procedure 11 and 7 128

4-nitro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.19 LC 559.21 [M + H]⁺ Procedure 11 and 7 129

2,5-difluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.19 LC 550.21 [M + H]⁺ Procedure 11 and 7 130

3,4-difluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.22 LC 550.2 [M + H]⁺ Procedure 11 and 7 131

3-cyano-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.10 LC 539.2 [M + H]⁺ Procedure 11 and 7 132

3,5-difluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.24 LC 550.21 [M + H]⁺ Procedure 11 and 7 133

(S)-1-oxo-1-(2-phenyl-1,1- bis(3-(trilfuoromethyl)phenyl)ethylamino)propan-2-yl acetate 4.04 LC 524.23 [M + H]⁺ Procedure 11 and7 134

4-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)-1,2,3-thiadiazole-5-carboxamide 4.14 LC 536.2 [M + H]⁺ Procedure 11 and7 135

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)thiophene-3-carobxamide 4.10 LC 520.17 [M + H]⁺ Procedure 11 and 7 136

2-phenyl-N-(2-phenyl-1,1- bis(3- (trilfuoromethyl)phenyl)ethyl)butanamide 4.29 LC 556.26 [M + H]⁺ Procedure 11 and 7 137

2-oxo-2-(2-phenyl-1,1-bis(3- (trilfuoromethyl)phenyl) ethylamino)ethylacetate 4.00 LC 510.2 [M + H]⁺ Procedure 11 and 7 138

2,3-difluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.16 LC 550.14 [M + H]⁺ Procedure 11 and 7 139

5-nitro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)furan-2-carobxamide 4.11 LC 549.16 [M + H]⁺ Procedure 11 and 7 140

4-methyl-3-nitro-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.23 LC 573.21 [M + H]⁺ Procedure 11 and 7 141

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)benzo[b]thiophene-2- carboxamide 4.29 LC 570.17 [M + H]⁺ Procedure 11and 7 142

6-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)nicotinamide 4.15 LC 549.17 [M + H]⁺ Procedure 11 and 7 143

2,4,5-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.24 LC 568.2 [M + H]⁺ Procedure 11 and 7 144

3-cyclohexyl-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)propanamide 4.44 LC 548.27 [M + H]⁺ Procedure 11 and 7 145

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)isoxazole-5-carboxamide 4.00 LC 505.18 [M + H]⁺ Procedure 11 and 7 146

3-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)thiophene-2-carboxamide 4.22 LC 554.12 [M + H]⁺ Procedure 11 and 7 147

2-chloro-4-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.18 LC 566.15 [M + H]⁺ Procedure 11 and 7 148

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)thiophene-2-carboxamide 4.15 LC 534.19 [M + H]⁺ Procedure 11 and 7 149

2-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)isonicotinamide 4.17 LC 549.17 [M + H]⁺ Procedure 11 and 7 150

3-chloro-4-fluoro-N-(2-phenyl- 1,1-bis(3-(trilfuoromethyl)phenyl)ethyl)benzamide 4.30 LC 566.15 [M + H]⁺ Procedure 11 and 7 151

3,4,5-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.33 LC 568.15 [M + H]⁺ Procedure 11 and 7 152

N-(2-phenyl-1,1-bis(3- (trilfuoromethyl)phenyl)ethyl)-2H-chromene-3-carboxamide 4.31 LC 568.17 [M + H]⁺ Procedure 11 and 7 153

N-(2-phenyl-1,1-bis(3- (trilfuoromethyl)phenyl)ethyl)benzofuran-5-carboxamide 4.17 LC 554.16 [M + H]⁺ Procedure 11 and 7 154

2-chloro-6-methyl-N-(2-phenyl- 1,1-bis(3-(trilfuoromethyl)phenyl)ethyl)isonicotinamide 4.23 LC 563.15 [M + H]⁺ Procedure 11 and 7155

2,3,4-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.23 LC 568.12 [M + H]⁺ Procedure 11 and 7 156

3-fluoro-4-methyl-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.24 LC 546.15 [M + H]⁺ Procedure 11 and 7 157

2-chloro-6-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.11 LC 566.13 [M + H]⁺ Procedure 11 and 7 158

5-chloro-2-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.27 LC 566.09 [M + H]⁺ Procedure 11 and 7 159

2,6-difluoro-3-methyl-N-(2- phenyl-1,1-bis(3-(trifluoromethyl)phenyl)ethyl) benzamide 4.13 LC 564.15 [M + H]⁺Procedure 11 and 7 160

4-phenyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)butanamide 4.30 LC 556.21 [M + H]⁺ Procedure 11 and 7 161

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)benzo[b]thiophene-3- carboxamide 4.28 LC 570.12 [M + H]⁺ Procedure 11and 7 162

2,4,6-trifluroo-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.12 LC 568.11 [M + H]⁺ Procedure 11 and 7 163

2,3,6-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.11 LC 568.15 [M + H]⁺ Procedure 11 and 7 164

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)pentanamide 4.24 LC 508.26 [M + H]⁺ Procedure 11 and 7 165

4-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)pentanamide 4.25 LC 508.19 [M + H]⁺ Procedure 11 and 7 166

methyl 5-oxo-5-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethylamino)pentanoate 4.06 LC 538.2 [M + H]⁺ Procedure 11 and 7 167

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) pivalamide 4.18 LC494.19 [M + H]⁺ Procedure 11 and 7 168

2-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)-5-(trifluoromethyl)benzamide 4.26 LC 600.1 [M + H]⁺ Procedure 11 and 7169

2-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)butanamide 4.16 LC 494.19 [M + H]⁺ Procedure 11 and 7 170

4-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide 4.30 LC 600.12 [M + H]⁺ Procedure 11 and 7171

2-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)pentanamide 4.22 LC 508.26 [M + H]⁺ Procedure 11 and 7 172

3-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)-5-(trifluoromethyl)benzamide 4.35 LC 600.2 [M + H]⁺ Procedure 11 and 7173

2,3,5-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.22 LC 568.11 [M + H]⁺ Procedure 11 and 7 174

3,4-dimethyl-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.26 LC 542.2 [M + H]⁺ Procedure 11 and 7 175

3,3,3-trifluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)propanamide 4.07 LC 520.14 [M + H]⁺ Procedure 11 and 7 176

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)furan-3-carboxamide 4.06 LC 504.15 [M + H]⁺ Procedure 11 and 7 177

4-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)oxazole-5-carboxamide 4.06 LC 504.15 [M + H]⁺ Procedure 11 and 7 178

2-(dimethylamino)-N-(2- phenyl-1,1-bis(3- (trilfuoromethyl)phenyl)ethyl)acetamide 3.50 LC 495.22 [M + H]⁺ Procedure 11 and 7 179

3-methoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)propanamide 4.06 LC 496.19 [M + H]⁺ Procedure 11 and 7 180

2,4-dimethyl-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.23 LC 542.19 [M + H]⁺ Procedure 11 and 7 181

2-(3,5-difluorophenyl)-N-(2- phenyl-1,1-bis(3-(trifluoromethyl)phenyl)ethyl) acetamide 4.21 LC 564.15 [M + H]⁺Procedure 11 and 7 182

3-chloro-2-fluoro-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)-5- (trifluoromethyl)benzamide 4.38 LC 634.17 [M + H]⁺Procedure 11 and 7 183

1-ethyl-3-methyl-N-(2-phenyl- 1,1-bis(3-(trifluoromethyl)phenyl)ethyl)-1H-pyrazole-5- carboxamide 4.17 LC 546.27 [M + H]⁺Procedure 11 and 7 184

1,5-dimethyl-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)-1H-pyrazole-3- carboxamide 4.09 LC 532.27 [M + H]⁺Procedure 11 and 7 185

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)benzamide 4.20 LC 528.26 [M + H]⁺ Procedure 11 and 7 186

2-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide 4.23 LC 600.17 [M + H]⁺ Procedure 11 and 7187

2,6-difluoro-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.07 LC 550.17 [M + H]⁺ Procedure 11 and 7 188

3-phenyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)propanamide 4.25 LC 542.26 [M + H]⁺ Procedure 11 and 7 189

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) propionamide 4.06LC 466.25 [M + H]⁺ Procedure 11 and 7 190

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)cyclohexanecarboxamide 4.26 LC 520.26 [M + H]⁺ Procedure 11 and 7 191

2-((2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) carbamoyl)phenylacetate 4.07 LC 572.22 [M + H]⁺ Procedure 11 and 7 192

3-fluoro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.17 LC 532.21 [M + H]⁺ Procedure 11 and 7 193

ethyl 3-oxo-3-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethylamino)propanoate 4.10 LC 539.2 [M + H]⁺ Procedure 11 and 7 194

4-cyano-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.10 LC 539.2 [M + H]⁺ Procedure 11 and 7 195

2-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.13 LC 548.17 [M + H]⁺ Procedure 11 and 7 196

2-methoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.21 LC 544.2 [M + H]⁺ Procedure 11 and 7 197

4-chloro-N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl) benzamide4.25 LC 548.16 [M + H]⁺ Procedure 11 and 7 198

ethyl 5-oxo-5-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethylamino)pentanoate 4.11 LC 552.26 [M + H]⁺ Procedure 11 and 7 199

3,3-dimethyl-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)butanamide 4.23 LC 508.26 [M + H]⁺ Procedure 11 and 7 200

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)-2-(thiophen-2-yl)acetamide 4.14 LC 534.18 [M + H]⁺ Procedure 11 and 7201

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)but-2-enamide 4.14 LC 492.26 [M + H]⁺ Procedure 11 and 7 202

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)cyclopropanecarboxamide 4.07 LC 478.23 [M + H]⁺ Procedure 11 and 7 203

3-methyl-N-(2-phenyl-1,1- bis(3- (trifluoromethyl)phenyl)ethyl)butanamide 4.17 LC 494.26 [M + H]⁺ Procedure 11 and 7 204

2-methoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)acetamide 4.03 LC 482.25 [M + H]⁺ Procedure 11 and 7 205

3-methoxy-N-(2-phenyl-1,1- bis(3-(trifluoromethyl)phenyl)ethyl)benzamide 4.15 LC 544.27 [M + H]⁺ Procedure 11 and 7 206

N-(2-phenyl-1,1-bis(3- (trifluoromethyl)phenyl)ethyl)thiophene-2-carboxamide 4.09 LC 520.2 [M + H]⁺ Procedure 11 and 7

TABLE 6 Retention Time Min./ Ex. Molecular Procedure No CompoundStructure Compound Name Mass of Ex. 207

N-(4-fluoro-3- (trifluoromethyl)benzyl)-2- phenyl-1,1-bis(3-(trifluoromethoxy)phenyl) ethanamine 4.51 LC No obs. [M + H]⁺ Procedure11 and 13

Additional compounds of the present invention were prepared by thegeneral procedures analogous to those described above and to theadditional general procedures described below.

Example 208

(R)-methyl3-(3,3,3-trifluoro-2-hydroxypropylamino)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoateProcedure 14 (R)-methyl3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate

(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamidewas prepared as described for Procedure 11. Under an argon atmosphere,CH₃COOMe (0.70 mL, 8.83 mmol, 2.0 eq) was stirred in anhydrous Et₂O (50mL) in an oven-dried round bottomed flask at −78° C. LDA (2.0 M, 4.4 mL,8.8 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirredat −78° C. for 30 min.(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(2.0 g, 4.42 mmol) in Et₂O (10 mL) was added dropwise to the abovestirred solution. The reaction mixture was stirred at −78° C. for 1.5 h.Saturated NH₄Cl was added, followed by the addition of EtOAc. Theorganic layer was washed with H₂O and brine, dried over Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashchromatography (silica gel, EtOAc/Hexanes=0 to 100%) to giveN-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)-ethyl)-2-methylpropane-2-sulfinamideas light tan oil (1.96 g, yield: 84.1%). LC-MS (ESI) 528.34 (M+H),retention time=4.00 min (10-90% MeOH in H₂O with 0.1% TFA in a 4-minrun); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.36 (d, J=8.0 Hz, 2H), 7.31 (t,J=8.0 Hz, 1H), 7.25-7.18 (m, 2H), 7.14-7.05 (m, 3H), 6.14 (s, 1H), 3.93(d, J=16.1 Hz, 1H), 3.54 (d, J=15.9 Hz, 1H), 3.86 (m, 2H), 3.49 (s, 3H),1.26 (s, 9H). ¹³C NMR (400 MHz, CDCl₃) ppm 22.71, 43.84, 51.68, 56.41,63.69, 118.63, 119.52, 120.49, 121.35, 124.27, 125.73, 129.81, 129.92,143.83, 147.52, 149.33, 171.93.

Methyl 3-amino-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate

Using the same procedure as that of Procedure 6, methyl3-amino-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate was obtained.LC-MS (ESI) 407.16 (M-NH₃+H), retention time=3.18 min (10-90% MeOH inH₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDC₃) δ ppm7.18-7.27 (m, 6H), 7.02 (d, J=8.07 Hz, 2H), 3.47 (s, 3H), 3.17 (s, 2H).

(R)-methyl3-(3,3,3-trifluoro-2-hydroxypropylamino)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate

Using a similar procedure to that described in Procedure 8, (R)-methyl3-(3,3,3-trifluoro-2-hydroxypropylamino)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoatewas obtained. LC-MS (ESI) 536.29 (M+H), retention time=3.93 min (10-90%MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm7.38-7.35 (m, 2H), 7.24-7.19 (m, 2H), 7.13 (m, 4H), 3.44 (s, 3H),3.22-3.35 (m, 2H), 2.57-2.74 (m, 2H).

Example 209

1-cyclopentyl-3-(2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureaProcedure 15

(R)-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamide(prepared as described for Procedure 11, 0.70 g, 1.33 mmol) wasdissolved in 8N NH₃ in ethylene glycol (6 mL) at room temperature in amicrowave vial. The reaction mixture was heated at 120° C. for 1200 sec,and then at 130° C. for 1200 sec under microwave irradiation. Aftercooling, the cap was removed, and H₂O was added. The mixture wasextracted with EtOAc (3×), washed with H₂O and brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography (silica gel, hexanes/EtOAc, then 10% MeOH in EtOAc) togive3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)-propanamideas white solid (0.52 g, yield: 76%) LCMS: 3.88 min [M+1]513.28 (4 mingradient, MeOH/H₂O 0.1% TFA); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.40-7.29(m, 3H), 7.22-7.12 (m, 3H), 7.11-7.02 (m, 2H), 6.29 (m, 2H), 5.40 (s,br, 1H), 3.78 (d, J=14.50 Hz, 1H), 3.71 (s, 2H), 3.35 (d, J=14.50 Hz,1H), 1.21-1.28 (m, 9H).

Procedure 16(R)-2-methyl-N-(2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

(R)-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamide(Procedure 15, 0.21 g, 0.41 mmol) was stirred in N,N-dimethylformamidedimethylacetal (6 mL) at room temperature for 1.5 h, then 60° C. for 20min. The solvent was evaporated to give crudeN-(5-(dimethylamino)-3-oxo-1,1-bis(3-(trifluoromethoxy)phenyl)pent-4-enyl)-2-methylpropane-2-sulfinamide.LC-MS (ESI) 568.4 (M+H), retention time=3.60 min (10-90% MeOH in H₂Owith 0.1% TFA in a 4-min run). This brownish residue was dissolved inHOAc (2 mL), and methyl hydrazine (0.4 mL) was added. The resultingreaction mixture was heated at 60° C. for 1.5 h. After cooling, H₂O wasadded. It was extracted with EtOAc (2×), washed with sat'd NaHCO₃, H₂Oand brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by flash chromatography (silica gel, hexanes/EtOAc)to give2-methyl-N-(2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide(0.18 g, yield: 79.8%). LC-MS (ESI) 551.35 (M+H), retention time=3.99min (10-90% MeOH in H₂O with 0.1% TFA in a 4-min run);

2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)-ethanamine

Using the same procedure as that described in Procedure6,2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanaminewas obtained. LC-MS (ESI) 447.24 (M+H), retention time=2.90 min (10-90%MeOH in H₂O with 0.1% TFA in a 4-min run);

1-cyclopentyl-3-(2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)urea

Using the same procedure as described for Procedure2,1-cyclopentyl-3-(2-(2-methyl-2H-1,2,4-triazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureawas obtained. LC-MS (ESI) 558.43 (M+H), retention time=3.81 min (10-90%MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm7.44 (s, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.26 (m, 2H), 7.18 (m, 2H), 7.11(d, J=8.0 Hz, 2H), 6.96 (br, s, 1H), 4.56 (m, 1H), 3.87 (m, 1H), 3.73(s, 2H), 3.35 (s, 3H), 1.92-1.85 (m, 2H), 1.61-1.49 (m, 4H), 1.29-1.22(m, 2H).

Example 210

1-cyclopentyl-3-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureaProcedure 17(R)-2-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamidewas prepared as described for Procedure 11. Under an Argon atmosphere,3,5-dimethylisoxazole (0.20 mL) was stirred in anhydrous THF in anoven-dried round bottomed flask at −78° C. nBuLi (2.5 M in hexanes, 0.84mL, 2.1 mmol) was added dropwise. The resulting yellowish solution wasstirred at −78° C. for 2 h.N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(0.81 g, 1.8 mmol) in THF (2 mL) was added dropwise to the above stirredsolution. The reaction mixture was stirred at −78° C. for 5 h, thenslowly warmed up to room temperature overnight. Saturated NH₄Cl wasadded, followed by the addition of EtOAc. The organic layer was washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash chromatography (silica gel,EtOAc/Hexanes=0 to 100%, came out at 100% EtOAc) to give2-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamideas light tan viscous oil (0.14 g, yield: 13.5% with 0.55 g recovery ofthe starting material). LC-MS (ESI) 551.38 (M+H), retention time=3.98min (10-90% MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz,CDCl₃) δ ppm 7.49-7.40 (m, 2H), 7.37-7.28 (m, 1H), 7.19 (d, J=6.57 Hz,1H), 7.05-7.14 (m, 4H), 5.70 (s, 1H), 4.61 (s, 1H), 4.14 (d, J=14.40 Hz,1H), 3.88 (d, J=14.40 Hz, 1H), 2.26 (s, 2H), 2.13 (s, 3H), 1.26 (s, 9H).

2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine

Using the same procedure as that described for Procedure 6, the titledcompound was obtained. LC-MS (ESI) 447.35 (M+H), retention time=3.16 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run).

1-cyclopentyl-3-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)-phenyl)ethyl)urea

Using the same procedure as that described for Procedure 2, the titledcompound was obtained. LC-MS (ESI) 558.41 (M+H), retention time=3.98 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz,CDCl₃) δ ppm 7.39-7.35 (m, 2H), 7.28-7.26 (m, 2H), 7.15-7.13 (m, 4H),5.57 (s, 1H), 5.29 (m, 1H), 4.04 (s, 2H), 3.93 (m, 1H), 2.19 (s, 3H),1.92-1.89 (m, 2H), 1.64-1.59 (m, 4H), 1.35-1.26 (m, 2H).

Example 211

1-cyclopentyl-3-(2-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureaProcedure 18(R)-N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamidewas prepared as described for Procedure 11. Under an argon atmosphere,acetonitrile (0.46 mL, 8.84 mmol, 2.0 eq) was stirred in anhydrous Et₂O(40 mL) in an oven-dried round bottomed flask at −78° C. LDA (2.0 M,4.42 mL, 8.84 mmol, 2.0 eq) was added dropwise. The resulting mixturewas stirred at −78° C. for 30 min.(R)-N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(2.0 g, 4.42 mmol) in Et₂O (10 mL) was added dropwise to the abovestirred solution. The reaction mixture was stirred at −78° C. for 4 h.Sat'd NH₄Cl was added, followed by the addition of EtOAc. The organiclayer was washed with H₂O and brine, dried over Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flashchromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give(R)-N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamideas light tan oil (1.15 g, yield: 52.7% with 0.85 g recovery of thestarting material). LC-MS (ESI) 495.26 (M+H), retention time=3.84 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz,CDCl₃) δ ppm 7.40-7.35 (m, 2H), 7.29 (d, J=8 Hz, 1H), 7.21-7.16 (m, 4H),7.08 (m, 1H), 4.53 (s, 1H), 3.75 (d, J=16 Hz, 1H) 3.56 (d, J=16 Hz, 1H),1.21 (s, 9H).

Procedure 192-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

(R)-N-(2-Cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(140 mg, 0.28 mmol) was stirred in EtOH (3 mL) and NH₂OH in H₂O (3 mL)in a capped microwave tube. The mixture was heated in an oil bath at60-65° C. for 2 h. LC-MS (ESI) 528.42 (M+H), retention time=3.46 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run). The cap was removedand the solvents were concentrated. The residue was dissolved in CH₂Cl₂,washed with H₂O, dried over MgSO₄, filtered, and concentrated to givecrudeN′-hydroxy-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamidine.After drying under vacuum for 2 h, the residue was dissolved in CH₂Cl₂(5 mL). Et₃N (0.25 mL, mmol, eq) was added followed by the addition ofAc₂O (0.1 mL). The resulting mixture was stirred at room temperature for24 h. LC-MS (ESI) 570.49 (M+H), 592.49 (M+Na), retention time=3.92 min(10-90% MeOH in H₂O with 0.1% TFA in a 4-min run). CH₂Cl₂ (5 mL) wasadded. The organic layer was washed with H₂O, dried over MgSO₄,filtered, and concentrated to dryness to give colorless film (0.255 g).This residue was dissolved in HOAc (5 mL) and was heated at 90° C. for 4h. After cooling, H₂O was added. The mixture was extracted with CH₂Cl₂(2×) and the combined organic portion washed with sat'd NaHCO₃ (2×), H₂Oand brine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%)to give2-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamideas colorless oil (52 mg, total yield for 3 steps: 41%). LC-MS (ESI)441.29 (M-NH₂), retention time=3.14 min (10-90% MeOH in H₂O with 0.1%TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.26-7.19 (m, 5H),7.00 (m, 3H), 3.57 (s, 2H), 2.39 (s, 3H).

Using the same procedure described for Procedure2,1-cyclopentyl-3-(2-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)ureawas obtained after purification using reverse phase HPLC (30-90% MeOH inH₂O with 0.1% TFA in a 10 min gradient, came out 17.53-18.00 min). LC-MS(ESI) 559.25 (M+H), retention time=4.06 min (10-90% MeOH in H₂O with0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.36-7.28 (m,4H), 7.20 (m, 2H), 7.10 (m, 2H), 3.93 (m, 1H), 3.84 (s, 2H), 2.46 (s,3H), 1.89 (m, 2H), 1.56 (m, 4H), 1.28 (m, 2H).

Example 219

4,4,4-trifluoro-1-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethylamino)butan-2-olProcedure 20(R)-2-methyl-N-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

2-Picoline (0.20 mL, 2.0 mmol) was stirred in anhydrous Et₂O (20 mL) at0° C. under Argon. nBuLi (2.5 M in hexanes, 0.84 mL, mmol) was addeddropwise. The reaction mixture turned to dark brown, and stirred at 0°C. for 20 min, then at room temperature for 1 h. It was cooled back to0° C., and(R)-N-(bis(3-(trifluoromethoxy)phenyl)-methylene)-2-methylpropane-2-sulfinamide(prepared as described in Example 82, Procedure 11) (0.906 g, 2.0 mmol)in Et₂O (4.0 mL) was added dropwise. The mixture was stirred at 0° C.for 1 h. then at room temperature for 1 h. The reaction was quenched byaddition of sat'd NH₄Cl. EtOAc was added; the organic layer was washedwith H₂O and brine, dried (Na₂SO₄), filtered, and concentrated todryness. The residue was purified by flash chromatography (silica gel,EtOAc/Hexanes=0 to 100%) to give2-methyl-N-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)-ethyl)propane-2-sulfinamideas light tan solids (0.19 g with recovery of 0.59 g of startingmaterial, yield: 48% based on recovery of the starting material). LC-MS(ESI) 547.38 (M+H), retention time=3.90 min (10-90% MeOH in H₂O with0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm 8.36-8.44 (m,1H), 7.90 (m, 1H), 7.51 (d, J=8.59 Hz, 1H), 7.37 (td, J=7.83, 2.27 Hz,2H), 7.19-7.24 (m, 2H), 7.11-7.17 (m, 3H), 6.98-7.07 (m, 2H), 6.75 (d,J=7.83 Hz, 1H), 4.15 (d, J=13.90 Hz, 1H), 3.81 (d, J=13.90 Hz, 1H),1.25-1.33 (m, 9H)

2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine

Using the same procedure described for Procedure6,2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine wasobtained. LC-MS (ESI) 444.38 (M+H), retention time=3.10 min (10-90% MeOHin H₂O with 0.1% TFA in a 4-min run);

4,4,4-trifluoro-1-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethylamino)butan-2-ol

Using the procedure described for Procedure8,4,4,4-trifluoro-1-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethylamino)butan-2-olwas obtained after purification via reverse phase HPLC to give pure(+/−)-4,4,4-trifluoro-1-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethylamino)butan-2-olas a TFA salt. LC-MS (ESI) 569.31 (M+H), retention time=3.21 min (10-90%MeOH in H₂O with 0.1% TFA in a 4-min run); ¹H NMR (400 MHz, CDCl₃) δ ppm8.65 (d, J=4.39 Hz, 1H), 7.63-7.70 (m, 1H), 7.41-7.47 (m, 1H), 7.34-7.38(m, 2H), 7.30-7.14 (m, 5H), 6.98 (m, 1H), 6.81 (d, J=7.91 Hz, 1H),4.47-4.53 (m, 1H), 3.86 (m, 2H), 2.84 (dd, J=12.08, 9.89 Hz, 1H), 2.67(dd, J=11.86, 2.64 Hz, 1H), 2.46 (m, 1H), 2.22 (m, 1H).

TABLE 7 Retention Time Min./ Ex. Molecular Prepared in the manner No.Structure Name Mass described in: 220

methyl 3-(4-fluoro-3- (trifluoromethyl)benzamido)- 3,3-bis(3-(trifluoromethoxy)phenyl) propanoate 4.10 LC 614.36 [M + H]⁺ Procedures11, 14 and 7 221

methyl 3-(3- cyclopentylureido)-3,3- bis(3-(trifluoromethoxy)phenyl)propanoate 4.02 LC 535.38 [M + H]⁺ Procedures 11, 14 and 2 222

1-cyclopentyl-3-(2-(2- methyl-2H-1,2,4-triazol-3- yl)-1,1-bis(3-(trilfuoromethoxy)phenyl) ethyl)urea 3.81 LC 558.43 [M + H]⁺ Procedures15, 16 and 2 223

N-(2-(2-methyl-2H-1,2,4- triazol-3-yl)-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl) cyclopropanecarboxamide 3.61 LC 515.33 [M + H]⁺ Procedures15, 16 and 7 224

(R)-1,1,1-trifluoro-3-(2-(2- methyl-2H-1,2,4-triazol-3- yl)-1,1-bis(3-(trifluoromethoxy)phenyl) ethylamino)propan-2-ol 3.73 LC 559.4 [M + H]⁺Procedures 15, 16 and 8 225

1-cyclopentyl-3-(2-(2,5- dimethyl-2H-1,2,4-triazol- 3-yl)-1,1-bis(3-(trifluoromethoxy)phenyl) ethyl)urea 3.73 LC 572.48 [M + H]⁺ Procedures15, 16 and 2 226

(R)-methyl-3-(3,3,3- trifluoro-2- hydroxypropylamino)-3,3-bis(3-(trifluoromethoxy) phenyl)propanoate 3.93 LC 536.29 [M + H]⁺Procedures 14 and 8 227

1-cyclopentyl-3-(2-(5- methyl-1,2,4-oxadiazol-3- yl)-1,1-bis(3-(trifluoromethoxy)phenyl) ethyl)urea 4.06 LC 559.25 [M + H]⁺ Procedures18, 19 and 2 228

1-cyclopentyl-3-(2-(pyridin- 2-yl)-1,1-bis(3- (trifluoromethoxy)phenyl)ethyl)urea 3.43 LC 554.4 [M + H]⁺ Procedures 20 and 2 229

1-cyclopentyl-3-(2-(3- methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy) phenyl)ethyl)urea 3.98 LC 558.41 [M + H]⁺Procedures 17 and 2 230

1-(3-fluorophenyl)-3-(2- (pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl) ethyl)urea 3.56 LC 580.33 [M + H]⁺ Procedures20 and 2 231

4,4,4-trifluoro-1-(2- (pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl) ethylamino)butan-2-ol 3.21 LC 569.31 [M + H]⁺Procedures 20 and 8 232

N-(1,1-bis(3- (trifluoromethoxy)phenyl) but-3-enyl)-4-fluoro-3-(trifluoromethyl)benzamide 581.402 Procedures 11 and 7

Example 233

(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideProcedure 21

(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared by analogous procedures described in Procedure 3, 4 and 5.The material was crystallized from CDCl₃ and an X-ray structureobtained.

TABLE 1 Properties of Crystal Forms CSD Refcode FORM Solvent Sites %Solvent ideal (w/w) HOT STAGE (° C.) D_(calc) (g/cc) Z V/Z sg T (° C.)62129116 N-1 None — 127-31 1.384 4 635 P4₁ −50

Example 234

7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoicProcedure 22

To a solution of ethyl hept-6-enoate (156 mg, 1 mmol) in dry THF (4 mL)cooled in an ice water bath was added a solution of 9-BBN (0.5 M in THF,2.0 mL, 1 mmol). The cooling bath was removed and the reaction mixturewas stirred for 1 h at room temperature. To the reaction mixture wasadded an aqueous solution of potassium phosphate (3 M, 0.66 mL, 2 mmol)and stirred for an additional 5 min. To the reaction mixture was added asolution of1-(3-bromophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine,prepared as described in Procedure 1, (0.2 M in THF, 3 mL, 0.6 mmol),followed by tris-(dibenzylideneacetone) dipalladium(0) (45 mg, 0.04mmol). The resulting yellow solution was heated under reflux for 20 h.The reaction mixture was cooled and concentrated under reduced pressure.The residue was extracted between water (10 mL) and ether (10 mL). Theether layer was washed twice with water, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography (2% to 10% EtOAc in Heptane) to yield ethyl7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate(169 mg, 54% yield). LCMS: RT=3.61 min, Purity 84% [M+H] 516.3(Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).

Procedure 23

To a solution of ethyl7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate(169 mg, 0.33 mmol) in anhydrous DCM (1 mL) was added cyclopentylisocyanate (22 mg, 0.2 mmol). The reaction mixture was stirred at rt for18 h. To the reaction mixture was added anhydrous THF (1 mL) and themixture was stirred at room temperature for additional 1 h. The solventswere evaporated on a rotary evaporator and the residue was dissolved inmethanol and purified by preparative HPLC (RT=11.3 min, Waters SunfireC18 OBD, 19×100 mm eluting with 26-90% MeCN/H₂O containing 0.1% TFA over9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220nm). The resulting solid was dissolved in methanol (1 mL) followed bythe addition of aqueous lithium hydroxide (1 N, 0.25 mL, 0.25 mmol). Thereaction mixture was heated at 36° C. for 18 h. The crude product waspurified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD,19×100 mm eluting with 18-90% MeCN/H₂O over 10 min and hold at 90% for 6additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm)to yield7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoicacid (Example 234, 32 mg, 53% yield for 2 steps). LCMS: RT=4.33 min,Purity >95%, [M+H] 599.4 (Sunfire-S5-C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.36 ppm, 1H, s; 7.16-7.24 ppm, 4H,m; 7.10-7.13 ppm, 3H, m; 6.97 ppm, 1H, d, J=7.7 Hz; 6.94 ppm, 1H, s;6.67 ppm, 2H, d, J=7.1 Hz; 5.58 ppm, 1H, brd, s; 3.87 ppm, 1H, d, J=12.6Hz; 3.83 ppm, 1H, m; 3.65 ppm, 1H, d, J=12.7 Hz; 2.54, 2H, t, J=7.5 Hz;2.29 ppm, 2H, t, J=7.4 Hz; 1.73-1.84 ppm, 2H, m; 1.50-1.60 ppm, 8H, m;1.15-1.36 ppm, 6H, m.

Example 235

(R)-6-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenyl-1-(3-(2,2,2-trifluoroethyl)ureido)ethyl)phenyl)hexanoicacid Procedure 24

To a solution of(R)-N-((S)-1-(3-bromophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(236 mg, 0.4 mmol), prepared as described in Procedure 3, 4, 5 and 6(67% yield), in anhydrous THF (1 mL) was added(6-ethoxy-6-oxohexyl)zinc(II) bromide (2.4 ml, 1.2 mmol) followed bytetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). Under Aratmosphere, the reaction mixture was heated to 130° C. under microwaveirradiation for 15 min. The residue was diluted with EtOAc (10 mL) andwashed with sat. NH₄Cl (2×5 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was dissolved in methanol and purified by preparative HPLC(Waters Sunfire C18 19×50 mm column eluting with 10-90% MeOH/H₂O over 7min; 20 mL/min, monitoring at 220 nm) to give ethyl6-(3-((R)-1-((R)-1,1-dimethylethylsulfinamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)phenyl)hexanoate(60 mg, 23% yield). LCMS: RT=3.97 min [M+H] 654.52 (4 min YMC-ODScolumn, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (500 MHz, CDCl₃) δ ppm7.24-7.33 (2H, m), 7.11-7.19 (5H, m), 6.89-6.94 (2H, m), 6.82 (1H, d,J=8.52 Hz), 6.67-6.73 (2H, m), 5.85 (1H, ttt, J=53.06, 2.61 Hz), 4.25(1H, s), 4.11 (2H, q, J=7.15 Hz), 4.03 (1H, d, J=12.65 Hz), 3.60 (1H, d,J=12.65 Hz), 2.59 (2H, dd), 2.26 (2H, t, J=7.56 Hz), 1.61 (4H, tt,J=15.77, 7.87 Hz), 1.28-1.34 (2H, m) 1.22-1.27 (3H, m), 1.20 (9H, s).

(R)-6-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenyl-1-(3-(2,2,2-trifluoroethyl)ureido)ethyl)phenyl)hexanoicacid (Example 235, 13 mg, 50% yield) was prepared as described inProcedure 6, 12 and 23. LCMS: RT=4.10 min [M+H] 647.30 (Sunfire-S5-C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (500 MHz, CDCl₃) δ ppm1.17-1.26 (m, 2H), 1.53-1.63 (m, 4H), 2.23-2.32 (m, 2H), 2.56 (t, J=7.15Hz, 2H), 3.60 (ddd, J=15.05, 9.14, 5.77 Hz, 1H), 3.66 (d, J=12.92 Hz,1H), 3.83 (ddd, J=15.67, 8.80, 7.15 Hz, 1H), 3.93 (d, J=12.92 Hz, 1H),5.09 (t, J=5.91 Hz, 1H), 5.64 (s, 1H), 5.86 (ttt, J=53.06, 2.61 Hz, 1H),6.69 (d, J=7.15 Hz, 2H), 6.87 (d, J=8.80 Hz, 1H), 6.90 (s, 1H), 6.96 (d,J=7.97 Hz, 1H), 6.99-7.02 (m, 2H), 7.06-7.12 (m, 3H), 7.16 (t, J=7.29Hz, 1H), 7.22 (t, J=7.70 Hz, 1H), 7.26 (s, 1H).

Example 236

1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 25

To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(20 mg, 0.047 mmol), prepared as described in Procedure 3, 4, 5 and 6,in THF (0.5 mL) was added K₂CO₃ in H₂O (10 mg, 2 M in H₂O, 0.071 mmol),followed by the addition of prop-1-en-2-yl carbonochloridate (6 pL,0.052 mmol). The reaction mixture was stirred at rt for 2 h, dilutedwith EtOAc (25 mL), washed with saturated NaCl (25 mL), dried overMgSO₄, filtered and concentrated under reduced pressure. To the residuewas added (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol (23mg, 0.094 mmol), prepared according to the procedure described in J.Org. Chem., 68(19):7545 (2003), TEA (20 μL, 0.14 mmol) in THF (0.5 mL).The reaction mixture was heated at 70° C. for 18 h. The reactionsolution was concentrated under reduced pressure and purified by ISCOchromatography (12 g column) using hexane/EtOAc (0-30% over 20 min) togive1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 236) as a white solid at a retention time of 17 min (19 mg, 59%yield). LCMS: RT=2.138 min [M+H] 701.29 (Phenomenex Luna C18 column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA, 5 mL/min, monitoring at 220 nm); HPLC: RT=4.335 min, Purity 94%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400MHz ¹H (CDCl₃) 7.37 ppm, 3H, m; 7.25 ppm, 3H, m; 7.20 ppm, 1H, t, J=7.03Hz; 7.13 ppm, 4H, m; 6.97 ppm, 2H, t, J=8.35 Hz; 6.89 ppm, 3H, m; 6.69ppm, 2H, d, J=7.47 Hz; 5.86 ppm, 1H, m; 5.18 ppm, 1H, d, J=8.35 Hz; 5.13ppm, 1H, s; 4.44 ppm, 2H, m; 4.26 ppm, 1H, d, J=9.67 Hz; 4.14 ppm, 1H,dd, J=8.13, 3.30 Hz; 3.99 ppm, 1H, m; 3.81 ppm, 2H, m; 3.71 ppm, 1H, m;3.59 ppm, 1H, m.

Example 237

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((2R,3R)-4,4,4-trifluoro-1,3-dihydroxybutan-2-yl)ureaProcedure 26

To a solution of1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 236, 17 mg, 0.024 mmol) in THF (1 mL) was added 20% Pd(OH)₂/C(8 mg) and the slurry was subjected to balloon hydrogenation for 18 h.The reaction mixture was filtered and the filtrate was concentrated andpurified by preparative HPLC (Shimadzu-YMC-ODS-A 5μ column, 30×100 mmeluting with 30-100% MeOH (90% in H₂O, 0.1% TFA) gradient over 12 minwith flow rate 40 mL/min and UV detection at 220 nm) to yield1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((2R,3R)-4,4,4-trifluoro-1,3-dihydroxybutan-2-yl)urea(Example 237) eluting at a retention time of 11.54 min as a clear oil(11 mg, yield 78%). LCMS: RT=1.983 min [M+H] 611.26 (Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA, 5 mL/min, monitoring at 220 nm); HPLC: RT=4.081 min, Purity100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂Oover 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm);NMR: 400 MHz ¹H (CDCl₃) 7.20 ppm, 1H, s; 7.16 ppm, 5H, m; 6.99 ppm, 2H,m; 6.91 ppm, 3H, m; 6.70 ppm, 2H, d, J=7.47 Hz; 5.87 ppm, 1H, m; 5.38ppm, 1H, d, J=7.47 Hz; 5.35 ppm, 1H, s; 4.28 ppm, 1H, d, J=5.71 Hz; 4.11ppm, 2H, m; 3.94 ppm, 2H, d, J=7.91 Hz; 3.82 ppm, 1H, m; 3.73 ppm, 1H,m; 3.67 ppm, 1H, d, J=8.35 Hz.

Example 238

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((S)-4,4,4-trifluoro-2-hydroxybutyl)ureaProcedure 27

To a solution of(R,R)-(−)-N′N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-hexanediamine(0.92 g, 1.53 mmol) in DCM (35 mL) was added TsOH H₂O (308 mg, 1.62mmol) and the reaction mixture was stirred at room temperature whileopen to air for 1 h. The reaction mixture was concentrated under reducedpressure and pentane was added to the residue. The resulting solid wasfiltered, rinsed with pentane once, diluted with DCM and transferred tothe reaction flask. DCM was then removed under reduced pressure and2-(2,2,2-trifluoroethyl)oxirane (37 g, 294 mmol) was added to theresulting solid. The mixture was cooled to 0° C. and H₂O (3.7 mL, 206mmol) was added dropwise. After addition was finished, the reactionmixture was stirred at room temperature for 72 h.(S)-2-(2,2,2-trifluoroethyl)oxirane was isolated as a clear oil (10 g,28%) by vacuum distillation from the reaction mixture into a cooled(−78° C.) receiving flask. NMR: 400 MHz ¹H (CDCl₃) 3.16 ppm, 1H, m; 2.87ppm, 1H, t, J=4.39 Hz; 2.59 ppm, 1H, dd, J=4.61, 2.42 Hz; 2.39 ppm, 1H,m; 2.29 ppm, 1H, m, J=10.44, 10.44, 5.05, 4.83 Hz.

The recovered epoxide was determined to be >99% ee according to theprocedure used by Jacobsen (J. Am. Chem. Soc., 124(7):1307-1315 (2004)).(Chiral HPLC analysis of the 2-napthylsulfide derivative (obtained byring opening with 2-napthalenethiol in MeOH using 1 equiv TEA and directanalysis of the product obtained, Chiralcel® AD, 95:5 hexanes:i-PrOH, 1mL/min, 254 nm, RT (minor)=16.52 min, RT (major)=19.28 min).

Procedure 28

To a solution of (S)-2-(2,2,2-trifluoroethyl)oxirane (2.00 g, 16.0 mmol)in a mixture of EtOH (16 mL) and H₂O (4 mL) were added NaN₃ (2.06 g,32.0 mmol) and NH₄Cl (1.70 g, 32.0 mmol). After stirring at roomtemperature for 18 h, the reaction mixture was diluted with H₂O (50 mL),extracted with Et₂O (2×75 mL). The combined organic layer was dried overMgSO₄, filtered and concentrated to give(S)-1-azido-4,4,4-trifluorobutan-2-ol as an oil (2.26 g, 83% yield).NMR: 400 MHz ¹H (CDCl₃) 4.17 ppm, 1H, ddd, J=6.81, 3.74, 3.52 Hz; 3.48ppm, 1H, m; 3.37 ppm, 1H, m; 2.35 ppm, 2H, m.

The crude (S)-1-azido-4,4,4-trifluorobutan-2-ol (2.26 g, 13.0 mmol) wassubjected to balloon hydrogenation for 18 h. After the filtration, thefiltrate was concentrated to give (S)-1-amino-4,4,4-trifluorobutan-2-ol(1.02 g, 45% yield). NMR: 400 MHz ¹H (CDCl₃) 3.88 ppm, 1H, m, J=7.85,7.85, 3.84, 3.74 Hz; 2.93 ppm, 1H, dd, J=12.74, 3.52 Hz; 2.61 ppm, 1H,dd, J=12.52, 8.13 Hz; 2.34 ppm, 1H, m; 2.21 ppm, 1H, m; 1.91 ppm, 3H, s.

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((S)-4,4,4-trifluoro-2-hydroxybutyl)urea(Example 238) was prepared as described in Procedure 25 (27 mg, 65%yield). LCMS: RT=2.02 min [M+H] 595.28 (Phenomenex Luna C18 column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA, 5 mL/min, monitoring at 220 nm); HPLC: RT=4.165 min, Purity 100%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.16 ppm, 5H, m; 6.94 ppm, 5H, m; 6.69 ppm, 2H,d, J=7.03 Hz; 5.73 ppm, 1H, m; 4.10 ppm, 2H, m; 3.93 ppm, 1H, s; 3.84ppm, 1H, m; 3.73 ppm, 1H, m; 3.52 ppm, 1H, s; 3.29 ppm, 1H, m; 3.04 ppm,1H, m; 2.17 ppm, 2H, m.

Example 239

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)ureaProcedure 29

To a 1:1 mixture of ether (1.85 mL) and 30% ammonium hydroxide (1.85 mL)was added drop-wise 2,2-bis(trifluoromethyl)oxirane (1.00 g, 5.5 mmol).The reaction mixture was stirred for 2 h at rt, then diluted with etherand H₂O. The aqueous layer was extracted twice with ether and thecombined ether layer was dried over MgSO₄, filtered and concentrated togive 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol as a semi solid(0.87 g, 81% yield). ¹H NMR (400 MHz, CDCl₃) ppm 3.14 (s, 2H), 3.25 (s,1H).

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)ureawas prepared as described in Procedure 12. The product was purified byISCO chromatography (4 g column) using hexane/EtOAc (0-20% over 12 min)to give the(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)urea(Example 239) as a colorless oil (24 mg, 65% yield). LCMS: RT=4.11 min[M+H] 649.10 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 3.60-3.90 (m, 4H), 5.13 (t, J=5.81 Hz,1H), 5.50 (s, 1H), 5.69-6.05 (t, J=56 Hz, 1H), 6.68 (d, J=6.82 Hz, 2H),6.81-6.95 (m, 3H), 6.96-7.05 (m, 3H), 7.06-7.24 (m, 5H).

Example 240

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(trifluoromethyl)cyclobutyl)ureaProcedure 30

To a solution of 1-(trifluoromethyl)cyclobutanecarboxylic acid (54 mg,0.354 mmol) in toluene (0.9 mL) was added TEA (36 mg, 0.354 mmol),followed by DPPA (76.4 uL, 0.354 mmol). The reaction mixture was heatedat 90° C. for 2 h, then allowed to cool to rt.(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(50 mg, 0.117 mmol), prepared as described in Procedure 3, 4, 5 and 6,was added and the reaction mixture was stirred at rt for 4.5 h. Thereaction mixture was concentrated under reduced pressure and purified byISCO chromatography (12 g column, eluting with 0-30% hexane/EtOAc over18 min). The product was further purified by preparative HPLC(Phenomenex AXIA Luna column, 30×100 mm, flow rate 40 mL/min, elutingwith 40-100% ACN/H₂O/0.1% TFA over 10 min) to yield(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(trifluoromethyl)cyclobutyl)urea(Example 240) as a white solid (45 mg, 65% yield). LCMS: RT=4.13 min[M+H] 519.18 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 1.83-2.06 (m, 2H), 2.16-2.33 (m, 2H),2.33-2.51 (m, 2H), 3.78 (qt, J=13 Hz, 2H), 4.71 (s, 1H), 5.02 (s, 1H),5.85 (t, J=52 Hz, 1H), 6.65-6.75 (m, 2H), 6.83-7.06 (m, 5H), 7.05-7.23(m, 5H).

Example 241

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)ureaProcedure 31

To a solution of (R)-methyl1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylate(112 mg, 0.2 mmol), prepared by the method described in Procedure 30, inTHF (0.2 mL) was added LiBH₄ (0.2 mL, 2 M in THF, 0.4 mmol) at roomtemperature. The reaction mixture was stirred for 14 h, then cooled to0° C. and 1 N HCl was added. The reaction mixture was diluted withether. The organic layer was washed with H₂O and sat. NaCl, dried overMgSO₄, filtered and concentrated to give a colorless oil. The resultingoil was purified by ISCO chromatography (4 g column, eluting with 0-100%hexane/EtOAc over 16 min) to yield(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)urea(Example 241) as a white foam (91 mg, 84% yield). LCMS: RT=2.97 min[M+H] 539.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%CH₃CN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min, monitoring at220 nm); ¹H NMR (400 MHz, CDCl₃) ppm 0.61-0.81 (m, 4H), 2.50 (brs, 1H),3.31-3.50 (m, 2H), 3.84 (qt, J=12 Hz, 2H), 4.93 (s, 1H), 5.84 (t, J=53Hz, 1H), 6.53-7.05 (m, 8H), 7.05-7.24 (m, 5H).

Example 242

(R)-1-(1-(cyanomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 32

To a solution of(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)urea(Example 241, 43 mg, 0.08 mmol) in ether (0.4 mL) was added PPh₃ (48 mg,0.18 mmol) and CBr₄ (58 mg, 0.18 mmol) at room temperature. The reactionmixture was stirred for 14 h and concentrated under reduced pressure andpurified by ISCO chromatography (4 g column, eluting with 0-15%hexane/EtOAc over 14 min) to yield(R)-1-(1-(bromomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaas a white solid (8 mg, 17% yield). LCMS: RT=4.06 min [M+H] 601.2(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR(400 MHz, CDCl₃) ppm 0.82-1.03 (m, 4H), 3.47 (qt, J=12 Hz, 2H), 3.81(ABqt, J=12 Hz, 2H), 5.01 (s, 1H), 5.39 (s, 1H), 5.86 (t, J=53 Hz, 1H),6.61-6.78 (m, 2H), 6.80-7.25 (m, 10H).

Procedure 33

To a solution of(R)-1-(1-(bromomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(8 mg, 0.013 mmol) in DMSO (0.3 mL) was added NaCN (18 mg, 0.37 mmol)and KI (20 mg, 0.12 mmol). The reaction mixture was stirred at rt for 3days. The reaction mixture was concentrated under reduced pressure andpurified by preparative HPLC (Phenomenex AXIA Luna column, 30×100 mm,flow rate 40 mL/min, 30-100% ACN/H₂O/0.1% TFA over 12 min) to yield(R)-1-(1-(cyanomethyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 242, 5 mg, 63% yield). LCMS: RT=3.88 min [M+H]548.3 (PhenomenexLuna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz,CDCl₃) ppm 0.76-0.91 (m, 4H), 2.58 (qt, J=17 Hz, 2H), 3.78 (qt, J=12 Hz,2H), 5.49 (s, 1H), 5.52 (s, 1H), 5.87 (t, J=53 Hz, 1H), 6.66 (d, J=6.6Hz, 2H), 6.84-6.95 (m, 3H), 6.96-7.07 (m, 2H), 7.07-7.26 (m, 5H).

Example 243

(R)-methyl2-(1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclopropyl)-2-oxoacetateProcedure 34

To a solution of(R)-1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylicacid (84 mg, 0.153 mmol), prepared by the method described in Procedure30, in DCM (0.5 mL) was added 2-(phenylphosphinylidene)acetonitrilecompound with biphenyl (1:1) (51 mg, 0.168 mmol), EDCI (32 mg, 0.168mmol) and DMAP (3 mg, 0.024 mmol). The reaction mixture was stirred atroom temperature for 4.5 h, concentrated under reduced pressure andpurified by ISCO chromatography (12 g column, eluting with 0-100%hexane/EtOAc) to yield(R)-1-(1-(2-cyano-2-(phenylphosphinylidene)acetyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureacompound with biphenyl (1:1) as a white solid (53 mg, 42% yield). LCMS:RT=3.49 min [M+H] 836.4 (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 50-100% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) ppm 0.78-1.00 (m, 2H),1.34-1.49 (m, 2H), 3.79-3.95 (m, 2H), 5.62-5.98 (m, 3H), 6.67-6.94 (m,7H), 6.98-7.20 (m, 5H), 7.37-7.66 (m, 15H).

A solution of(R)-1-(1-(2-cyano-2-(phenylphosphinylidene)acetyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureawith biphenyl (1:1) (53 mg, 0.063 mmol) in DCM/MeOH (0.7 mL/0.3 mL) wascooled to −78° C. O₃ was bubbled into the solution until the solutionbecame light blue. The reaction mixture was warmed to room temperatureand concentrated under reduced pressure. The resulting residue waspurified by ISCO chromatography (4 g column) using hexane/EtOAc (0-100%)to give (R)-methyl2-(1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclopropyl)-2-oxoacetate(Example 243) as a white solid (33 mg, 86% yield). LCMS: RT=2.99 min[M+H] 595.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-100%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 0.81-0.95 (m, 2H), 1.04-1.18 (m, 2H),3.63-3.88 (m, 5H), 5.48 (s, 2H), 5.86 (t, J=53 Hz, 1H), 6.60-6.69 (m,2H), 6.80-7.02 (m, 5H), 7.05-7.24 (m, 5H).

Example 244

(R)-methyl2,2-difluoro-2-(1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclopropyl)acetateProcedure 35

To a solution of (R)-methyl2-(1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclopropyl)-2-oxoacetate(Example 243, 24 mg, 0.040 mmol) in DCM (0.5 mL) at 0° C. was added DAST(40 mg, 0.24 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for 1 h. The reaction mixture was quenched byaddition of sat. NaHCO₃ (0.5 mL), concentrated under reduced pressureand purified by preparative HPLC (Phenomenex Axia column, 30×100 mm,flow rate 40 mL/min, 30-100% CH₃CN/H₂O/0.1% TFA over 13 min) to yield(R)-methyl2,2-difluoro-2-(1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclopropyl)acetate(Example 244) as a white solid (3 mg, 12% yield). LCMS: RT=2.12 min[M+H] 617.5 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 0.81-0.98 (m, 2H), 1.21-1.35 (m, 2H),3.62-3.94 (m, 5H), 4.96 (s, 1H), 5.57-6.08 (m, 2H), 6.61-6.72 (m, 2H),6.84-7.25 (m, 21H).

Example 245

(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylureaProcedure 36

To a solution of(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea(20 mg, 0.033 mmol), prepared as described in Procedure 3, 4, 5, 6 and2, in DMSO/THF (0.1 mL/0.1 mL) was added N-methylcyclopentanamine (32mg, 0.33 mmol). The resulting solution was stirred at 120° C. undermicrowave irradiation for 1800 sec. The reaction mixture was filteredand the solid was washed with EtOAc. The filtrate was then washed withH₂O, sat. NaCl and dried over Na₂SO₄. The organic solvent was evaporatedunder reduced pressure and the resulting residue was purified by prepHPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90%ACN/H₂O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at220 nm) to afford(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylurea(Example 246) as white lyophillate (13 mg, 65% yield). LCMS: [M+H] 619.2(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).

Example 246

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)ureaProcedure 37

To a solution of (1R,2R)-2-(benzyloxy)cyclopentanamine (3.5 g, 18.3mmol) in EtOH (20 mL) was added TFA (1.6 mL, 21.5 mmol), followed byPd(OH)₂/C (20% wt, 627 mg). The reaction mixture was degassed with Arand stirred at rt under H₂ atmosphere for 3 days. The resulting solidwas filtered and rinsed with EtOH. The filtrate was concentrated toyield (1R,2R)-2-aminocyclopentanol TFA salt (4.3 g, 100% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-D6) ppm 1.00-1.13 (m, 1H), 1.39-1.57(m, 2H), 1.56-1.76 (m, 2H), 1.79-1.94 (m, 1H), 1.94-2.10 (m, 1H),3.06-3.23 (m, 1H), 3.88-4.02 (m, 1H), 7.84-8.07 (m, 2H).

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)urea(Example 246) was prepared as described in Procedure 25. HPLC: RT=3.94min [M+H] 553.08 (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07-1.35 (m, 1H), 1.43-1.78(m, 3H), 1.80-1.98 (m, 2H), 3.42-3.60 (m, 1H), 3.61-3.73 (m, 1H),3.74-3.83 (m, 1H), 3.83-3.96 (m, 1H), 4.52-4.92 (m, 1H), 5.66-6.03 (m,2H), 6.64-6.77 (m, 2H), 6.80-6.89 (m, 1H), 6.89-7.04 (m, 4H), 7.04-7.22(m, 4H).

Example 247

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2S)-2-fluorocyclopentyl)ureaProcedure 38

To a solution of (1R,2R)-2-aminocyclopentanol TFA salt (630 mg, 2.93mmol) was added diphenylmethanimine (490 uL, 2.93 mmol) and TEA (0.5 mL,3.58 mmol) in CH₂Cl₂ (3 mL). The reaction mixture was stirred at rt for2 h and concentrated under reduced pressure and purified by ISCO flashchromatography using EtOAc and hexane as eluting solvent to yield(1R,2R)-2-(diphenylmethyleneamino)cyclopentanol (697 mg, 90% yield) as acolorless gum. HPLC: RT=1.96 min [M+H] 266.13 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm1.49-1.64 (m, 2H), 1.66-1.91 (m, 3H), 2.08-2.24 (m, 1H), 3.55-3.71 (m,1H), 4.31-4.47 (m, 1H), 7.15-7.25 (m, 2H), 7.29-7.53 (m, 6H), 7.61-7.67(m, 2H).

To a solution of (1R,2R)-2-(diphenylmethyleneamino)cyclopentanol (112mg, 0.42 mmol) in CH₂Cl₂ (1 mL) at −20° C. was added dropwise DAST (67uL, 0.5 mmol). The reaction mixture was allowed to warm up rt andstirred for 16 h. The solution was concentrated under reduced pressureto yield crude (1R,2R)-2-fluorocyclopentanamine (120 mg) which was usedto next step without further purification.

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2S)-2-fluorocyclopentyl)urea(Example 247) was prepared as described in Procedure 25. LCMS: RT=4.07min [M+H] 555.20 (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm); ¹H NMR (400 MHz, CD₃CN) δ ppm 1.02-1.12 (m, 6H), 3.15-3.33(m, 2H), 3.89 (dd, 2H), 5.10-5.24 (m, 1H), 6.22 (t, 1H), 6.71-6.82 (m,2H), 6.93-7.00 (m, 1H), 7.01-7.33 (m, 9H).

Example 248

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1r,3R)-3-formylcyclobutyl)ureaProcedure 39

To a suspension of(1r,3r)-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (217 mg,1 mmol) in CH₂Cl₂ (5 ml) at ambient temperature was added TFA (0.37 mL,2.7 mmol) in one portion, and the reaction mixture was stirred atambient temperature for 16 h, then concentrated to yield(1r,3r)-3-aminocyclobutanecarboxylic acid (227 mg, 100% yield) as acolorless oil. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.21-2.34 (m, 2H),2.35-2.46 (m, 2H), 3.01-3.17 (m, 1H), 3.65-3.85 (m, 1H), 7.90-8.13 (m,3H).

Using the method described in Procedure 25,(1R,3r)-3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclobutanecarboxylicacid was prepared as a white solid (372 mg, 66% yield). HPLC: RT=3.90min [M+H] 567.69 (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm).

Procedure 40

To a solution of(1R,3r)-3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)cyclobutanecarboxylicacid (180 mg, 0.32 mmol) in CH₂Cl₂ (5 mL) was addedN,O-dimethylhydroxyamine HCl (31 mg, 0.32 mmol) and N-methylmorpholine(32 mg, 0.37 mmol). The reaction mixture was cooled to −10° C. under Ar.After 5 min, EDCI (61 mg, 0.39 mmol) was added and the reaction mixturewas allowed to reach rt and stirred for 15 min. The reaction mixture wasconcentrated and purified by ISCO flash chromatography to yield(1R,3r)-3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-N-methoxy-N-methylcyclobutanecarboxamideas a white solid (194 mg, 100% yield). HPLC: RT=3.94 min [M+H] 610.72(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR(400 MHz, DMSO) ppm 2.55-2.63 (m, 2H), 2.94-3.10 (m, 2H), 3.61-3.71 (m,3H), 3.84-4.02 (m, 1H), 4.13-4.21 (m, 3H), 4.41 (dd, 2H), 4.58-4.75 (m,1H), 5.92-6.05 (m, 2H), 6.75 (t, 1H), 7.24-7.33 (m, 2H), 7.43-7.52 (m,2H), 7.54-7.64 (m, 3H), 7.64-7.83 (m, 5H).

Procedure 41

To a solution of(1R,3r)-3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-N-methoxy-N-methylcyclobutanecarboxamide(182 mg, 0.3 mmol) in THF (2 mL) at −78° C. under Ar was added dropwiseDIBAL-H (1.0 M in hexane, 0.75 mL). The reaction mixture was stirred at−78° C. for 20 min. Acetone (1 mL) was added, followed by saturatedaqueous potassium sodium tartrate (5 mL) and ether (2 mL). The resultingreaction mixture was stirred at rt for 16 h. The aqueous layer wasextracted with ether (2×10 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by ISCO flash chromatography using EtOAcand hexane as eluting solvent to yield1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1r,3R)-formylcyclobutyl)urea(Example 248) as a white solid (122 mg, 74% yield). HPLC: RT=3.89 min[M+H] 551.10 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.73-1.88 (m, 2H), 2.35-2.49 (m, 2H),2.80-2.94 (m, 1H), 3.64 (dd, 2H), 3.81-3.98 (m, 1H), 4.95 (d, 1H),5.20-5.29 (m, 1H), 5.79 (t, 1H), 6.56 (d, 2H), 6.71-6.92 (m, 4H),6.92-7.16 (m, 5H), 9.58-9.70 (m, 1H).

Example 249

1-((1r,3R)-3-(difluoromethyl)cyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 42

To a solution of1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1r,3R)-formylcyclobutyl)urea(Example 248, 43 mg, 0.078 mmol) in CH₂Cl₂ (0.5 ml) at rt was added DAST(30 uL, 0.23 mmol) dropwise. The reaction mixture was stirred at rt for16 h, concentrated under reduced pressure and purified by prep HPLC(phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H₂Oover 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm).The product was further purified by ISCO flash chromatography to yield1-((1r,3R)-3-(difluoromethyl)cyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 249) as a white solid (18 mg, 40% yield). HPLC: RT=4.03 min[M+H] 573.69 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (500 MHz, CD₃CN) δ ppm 1.98-2.08 (m, 2H), 2.24-2.39 (m, 2H),2.46-2.65 (m, 1H), 3.85 (dd, 2H), 4.08-4.22 (m, 1H), 5.45-5.56 (m, 1H),5.96 (t, 1H), 6.19 (t, 1H), 6.65-6.78 (m, 2H), 6.88-6.97 (m, 2H).

Example 250

1-((1r,3R)-3-acetylcyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 43

To a solution of(1R,3r)-3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-N-methoxy-N-methylcyclobutanecarboxamide,prepared as described in Procedure 40, (160 mg, 0.26 mmol) in ether (5mL) at −40° C., was added dropwise CH₃MgBr (3 M in ether, 0.2 mL). Thenthe reaction mixture was stirred at 0° C. for 4 h. The reaction wasquenched with sat. NaCl and the aqueous layer was extracted with ether.The combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting oil was purified byISCO flash chromatography using EtOAc and hexane as eluting solvent toyield1-((1r,3R)-3-acetylcyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 250) as a white solid (32 mg, 22% yield). HPLC: RT=3.90 min[M+H]565.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CD₃CN) δ ppm 2.03-2.09 (m, 2H), 2.08-2.12 (m, 3H),2.41-2.54 (m, 2H), 3.10-3.23 (m, 1H), 3.88 (dd, 2H), 3.98-4.07 (m, 1H),5.41-5.51 (m, 2H), 6.21 (t, 1H), 6.73-6.80 (m, 2H), 6.93-7.00 (m, 2H),7.02-7.10 (m, 3H), 7.12-7.30 (m, 6H).

Example 251

(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamideProcedure 44

To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(28 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, inDCM (1 mL) was added pyridine (0.01 mL, 0.12 mmol). The reaction wascooled to 0° C., followed by the addition of 4-methyleneoxetan-2-one(0.01 mL, 0.13 mmol). The reaction mixture was stirred at rt for 2 h andconcentrated. The residue was purified by preparative HPLC (Axia lunacolumn, 30×75 mm, 40-100% ACN/H₂O with 0.1% TFA over 10 min, flow rate40 mL/min, monitoring at 220 nm) to yield(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide(Example 251) as colorless oil (23 mg, 58% yield). LCMS: RT=3.71 min[M+H]510.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (1H, s), 7.04-7.20 (5H, m),6.96-7.02 (2H, m), 6.87-6.92 (3H, m), 6.61 (2H, d, J=7.07 Hz), 5.87 (1H,t, J=2.78 Hz), 3.94 (1H, d, J=12.88 Hz), 3.71 (1H, d, J=12.88 Hz), 3.43(2H, s), 2.24 (3H, s).

Example 252

1-((1R,3S)-3-((S)-fluoro(hydroxy)methyl)cyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 45

To a solution of1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1s,3S)-3-formylcyclobutyl)urea(Example 248, 35 mg, 0.064 mmol) in CH₂Cl₂ (0.5 ml) was added DAST (50uL, 0.37 mmol). The reaction mixture was stirred at rt for 3 days, thenconcentrated and purified by prep HPLC to yield1-((1R,3S)-3-((S)-fluoro(hydroxy)methyl)cyclobutyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 252) as a light yellow solid (20 mg, 56% yield). LCMS: RT=1.79min [M+H] 553.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.59-1.79 (m, 1H), 1.95-2.15(m, 1H), 2.52-2.77 (m, 2H), 2.90-3.07 (m, 1H), 3.65-3.76 (m, 2H),3.99-4.16 (m, 1H), 4.60-5.11 (m, 1H), 5.56-6.07 (m, 2H), 6.57-6.67 (m,2H), 6.78-7.32 (m, 12H), 10.13-10.41 (m, 1H).

Example 253

(R)-1-(2-cyano-2,2-difluoroethyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 46

To a suspension of zinec dust (238 mg, 3.66 mmol) in THF (3 ml) under Arwas added TMSCl (234 uL, 1.83 mmol). The reaction mixture was stirred atrt for min followed by addition of ethyl bromodifluoroacetate (260 uL,2.0 mmol) dropwise. After 10 min,N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzyl-1-phenylmethanaime(600 mg, 1.83 mmol) in THF (3 ml) was added and the reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedwith 5% NaHCO₃ in H₂O (10 mL). The resulting solid was filtered andwashed with EtOAc. The filtrate was extracted with EtOAc and thecombined EtOAc layers were dried over MgSO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by ISCO flashchromatography by using EtOAc and hexane as eluting solvent to yieldethyl 3-(dibenzylamino)-2,2-difluoropropanoate as a colorless oil (577mg, 56% yield). LCMS: RT=4.09 min [M+H] 334.28 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm).

To a solution of ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (517 mg,1.55 mmol) in EtOH (1 mL) was added 0.5 N HCl (1 mL) and Pd(OH)₂/C (20%,50 mg). The reaction mixture was stirred at room temperature under H₂atmosphere for 3 days. The reaction mixture was filtered and the solidwas rinsed with water and ether. The aqueous layer was separated fromthe ether layer and lyophilized to yield ethyl3-amino-2,2-difluoropropanoic acid as a white solid (210 mg, 100%yield). ¹H NMR (400 MHz, DMSO) ppm 3.27-3.46 (m, 2H), 8.06-8.64 (m, 3H).

Using the method described in Procedure 25,(R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoicacid (60 mg, 0.1 mmol) was prepared as a white solid (62 mg, 54% yield).LCMS: RT=1.97 min [M+H] 577.2 (Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm).

Procedure 47

To a solution of(R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoicacid (60 mg, 0.1 mmol) in CH₂Cl₂ (1 mL) at 0° C. was added ethylcarbonochloridate (10 uL, 0.1 mmol), followed by NEt₃ (0.021 mL, 0.15mmol) and NH₃*H₂O (0.1 mL, 2.6 mmol). The reaction mixture was stirredat rt for 30 min, then concentrated under reduced pressure and purifiedby prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with10-90% ACN/H₂O over 10 minutes containing 0.1% TFA; 40 mL/min,monitoring at 220 nm) to yield(R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamideas a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).

Procedure 48

To a solution of(R)-2,2-difluoro-3-(3-(1-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide(12 mg, 0.02 mmol) in CH₂Cl₂ (0.5 mL) at −78° C. was added DMSO (10 uL,0.14 mmol), followed by addition of (COCl)₂ (2 M in CH₂Cl₂, 0.05 mmol).The reaction mixture was stirred at −78° C. for 15 min, then NEt₃ (0.03mL, 0.2 mmol) was added dropwise. The reaction mixture was allowed towarm to rt and stirred for 16 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified by prep HPLC(Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H₂Oover 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) toyield(R)-1-(2-cyano-2,2-difluoroethyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 253) as a white solid (7 mg, 62% yield). LCMS: RT=4.03 min[M+H] 558.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.71 (d, 2H), 3.76-3.99 (m, 3H),4.75-4.84 (m, 1H), 5.13-5.27 (m, 1H), 5.86 (t, 1H), 6.64-6.76 (m, 2H),6.86-6.96 (m, 3H), 6.97-7.06 (m, 2H), 7.07-7.23 (m, 5H).

Example 254

(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 49

To a solution of 3-bromo-5-fluorophenol (5.7 g, 30 mmol), prepared asdescribed in Procedure 3, and imidazole (4.0 g, 60 mmol, 2 eq) inanhydrous THF (100 mL) at 0° C. was added tert-butyldiphenyl-silylchloride (9.6 mL, 1.3 eq). The resulting mixture was stirred at roomtemperature for 18 h. The reaction mixture was quenched with water andextracted with hexane/EtOAc (1:1). The combined organic layers werewashed with H₂O (2×) and sat. NaCl (2×), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (hexanes/EtOAc) to give(3-bromo-5-fluorophenoxy)(tert-butyl)diphenylsilane as colorless oil(7.5 g, yield 58%).

(R)-1-(1-(3-(tert-butyldiphenylsilyloxy)-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureawas prepared as described in Procedure 4, 5, 6 and 10 (85 mg, 37%overall yield). LCMS: RT=2.71 min [M+H] 757.3 (Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA; 5 mL/min, monitoring at 220 nm).

To a solution of(R)-1-(1-(3-(tert-butyldiphenylsilyloxy)-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(85 mg, 0.11 mmol) in THF (1.5 mL) was added TBAF (1.0 M in THF, 0.12mL, 0.12 mmol). The resulting mixture was stirred at room temperaturefor 45 min. The reaction was diluted with CH₂Cl₂ and washed with sat.NH₄Cl, H₂O and sat. NaCl, dried over Na₂SO₄, filtered and concentrated.The resulting residue was purified by flash chromatography (silica gel,hexanes/EtOAc) to give(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 254, 45 mg, yield 77%). LCMS: RT=2.0 min [M+H] 519.1(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.20-7.27 (3H, m), 7.09-7.18 (3H, m), 6.72 (1H,d, J=9.60 Hz), 6.66 (3H, d, J=7.07 Hz), 6.57 (1H, s), 3.73-3.78 (1H, m),3.65-3.71 (1H, m), 3.63 (1H, d, J=8.59 Hz), 3.47-3.58 (1H, m).

Example 255

(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 50

To a solution of(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 254, 15 mg, 0.03 mmol) in DMSO (0.15 mL) was added ICH₂CF₃(0.02 mL) and K₂CO₃ (20 mg, 0.2 mmol). The reaction mixture was heatedat 70° C. overnight. The reaction was cooled to rt and diluted withCH₃CN, filtered and purified by prep HPLC (phenomenex AXIA Luna 75×30mm, 5μ column eluting with 10-90% ACN/H₂O over 10 minutes containing0.1% TFA; 40 mL/min, monitoring at 220 nm) to give(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 255) as white solid (10 mg, yield 58%). LCMS: RT=2.18 min [M+H]601.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.33-7.43 (2H, m), 7.21 (1H, d,J=6.60 Hz), 7.12-7.19 (2H, m), 6.68 (2H, d, J=7.70 Hz), 6.54-6.63 (3H,m), 4.19-4.30 (2H, m), 3.73-3.84 (4H, m).

Example 256

(R)-1-(1-(3-cyano-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 51

To a solution of(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 254, 0.12 g, 0.23 mmol) in anhydrous CH₂Cl₂ (2 mL) at 0° C.under argon was added Et₃N (0.05 mL, 0.4 mmol) followed by dropwiseaddition of trifluoroacetic anhydride (0.05 mL). The reaction mixturewas stirred at 0° C. for 30 min the diluted with CH₂Cl₂ (10 mL). Theorganic layer was washed with H₂O, sat. NaCl, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, hexanes/EtOAc) to give(R)-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(2,2,2-trifluoroethyl)ureido)ethyl)phenyltrifluoromethanesulfonate (65 mg). LCMS: RT=2.34 min [M+H] 651.4(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). To asolution of(R)-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(2,2,2-trifluoroethyl)ureido)ethyl)phenyltrifluoromethanesulfonate (65 mg, 0.1 mmol) in DMF (0.4 mL) was addedZn(CN)₂ (70 mg) and Pd(PPh₃)₄ (catalytic amount). The reaction mixturewas heated to 105° C. in a sealed vial for 2 h. After cooling to rt, thereaction solution was filtered and the solid was rinsed with EtOAc. Thefiltrate was washed with sat. NaHCO₃, H₂O, and sat. NaCl, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (silica gel, hexanes/EtOAc)to give(R)-1-(1-(3-cyano-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 256, 37 mg, 30% yield for 2 steps). LCMS: RT=3.88 min [M+H]528.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.31 (m, 2H), 7.26-7.13 (m, 4H),7.02-6.93 (m, 3H), 6.66 (d, J=7.7 Hz, 2H), 5.24 (s, br, 1H), 5.05 (t,J=6.0 Hz, 1H), 3.80 (AB, J=12.6 Hz, 2H), 3.74 (m, 2H).

Example 257

(R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 52

To a solution of(S)-1-(1-(3-cyanophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 256, mg, 0.06 mmol) in THF (1 mL) at rt was added CH₃MgBr (3.0M in Et₂O, 0.1 mL). The reaction mixture was heated at 48° C.-55° C. for2.5 h. After cooling, 1N HCl was added and the reaction mixture wasstirred for 10 min at rt. The reaction mixture was extracted with EtOAc,washed with H₂O, sat. NaCl, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by flashchromatography (silica gel, hexanes/EtOAc) to give pure(R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 257, 26 mg, yield: 84%). LCMS: RT=3.90 min [M+H] 545.2(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.58 (m, 1H), 7.53 (m, 1H), 7.36 (m, 2H), 7.23(m, 1H), 7.16 (m, 4H), 6.68 (d, J=6.8 Hz, 2H), 5.43 (s, br, 1H), 5.17(m, 1H), 3.88 (dd, J=23.2, 12.9 Hz, 2H), 3.78 (m, 2H), 3.03 (s, 3H).

Example 258

(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 53

To a solution of(R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 257, mg, 0.037 mmol) in THF (1 mL) at 0° C. under argon wasadded dropwise CH₃Li (1.4 M in Et₂O, 0.04 mL, 0.056 mmoL). The reactionmixture was stirred at room temperature for 2 h, then quenched with sat.NH₄Cl and 0.5 N HCl and the aqueous layer was extracted with EtOAc. Thecombined organic portions were washed with H₂O, sat. NaCl, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, hexanes/EtOAc) to give(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 258, 8 mg, yield 39%). LCMS: RT=3.89 min [M+H] 559.4(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% NH₄Cl; 4 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CDCl₃) ppm 7.51-7.45 (m, 2H), 7.21-6.96 (m, 6H), 6.68 (d,J=6.8 Hz, 2H), 6.61 (d, J=9.9 Hz, 1H), 5.43 (s, br, 1H), 5.17 (m, 1H),4.01 (d, J=13.2 Hz, 1H), 3.85-3.62 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H).

Example 259

(1S,4R)-methyl3,3-difluoro-4-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetra-fluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-)ureido)cyclopentanecarboxylateProcedure 54

To a solution of (1S,3R,4R)-methyl3-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-4-hydroxycyclopentanecarboxylate,prepared as described Procedure 12, (11 mg, 0.017 mmol) in acetone (430μL) was added a solution of Jones reagent (17 μL, 1 M solution). Thereaction mixture was stirred at rt for 1.5 h, then filtered through acelite pad. The pad was washed with acetone and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in EtOAcand the solution was washed with H₂O. The organic layer was separatedand the aqueous layer was further extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was dissolved in CH₂Cl₂ (17 mL) andDAST (6.5 mL) was added at rt. The reaction mixture was stirredovernight, then quenched with sat. NaCl. The aqueous layer was extractedwith CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting withMeCN/H₂O containing 0.1% TFA, monitoring at 220 nm) to provide(1S,4R)-methyl3,3-difluoro-4-(3-((R)-1-(3-fluoro-5-(1,1,2,2-tetra-fluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-)ureido)cyclopentanecarboxylate(Example 259, 9 mg, 85% yield) as a film. ¹H NMR (500 MHz, CDC₃) δ7.16-7.07 (m, 6H), 7.00-6.83 (m, 6H), 6.62 (d, J=10 Hz, 2H), 5.93-5.68(m, 1H), 5.37 (s, 1H), 3.77 (d, J=10 Hz, 1H), 3.64 (s, 3H), 3.68-5.58(m, 2H), 2.90-2.84 (m, 1H), 2.47-2.26 (m, 3H), 1.60-1.53 (m, 1H); LC/MS:RT=3.97 min [M+H] 631.4 (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeCN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min,monitoring at 220 nm).

Example 260

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)ureaProcedure 55

To a solution of(R)-1-(5-cyanopentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea,prepared by the method described in Procedure 12 (45 mg, 0.080 mmol) inDME (161 μL) at rt was added TMSN₃ (0.013 mL, 0.16 mmol), followed byn-Bu₂SnO₂ (2 mg, 0.008 mmol). The reaction mixture was heated at 150° C.for 10 min under microwave irradiation. An additional amount of TMSN₃(0.013 mL, 0.16 mmol) and n-Bu₂SnO₂ (2 mg, 0.008 mmol) was added, andthe reaction mixture was heated at 150° C. for an additional 10 minunder microwave irradiation. The reaction mixture was concentrated andthe residue was dissolved in MeOH and purified by preparative HPLC(Phenoma Luna AXIA 10A, C18, eluting with MeCN/H₂O containing 0.1% TFA,monitoring at 220 nm) to provide(R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(23 mg, 47% yield) as a white solid. ¹H NMR (500 MHz, MeOH-d₄) δ7.18-6.89 (m, 11H), 6.71 (d, J=5 Hz, 2H), 6.37-6.16 (m, 1H), 3.93 (d,J=15 Hz, 1H), 3.81 (d, J=15.0 Hz, 1H), 3.08 (t, J=5Hz, 2H), 2.94 (t,J=5Hz, 2H), 1.83-1.76 (m, 2H), 1.55-1.48 (m, 2H), 1.41-1.35 (m, 2H);LC/MS: RT=3.736 min [M+H] 607.3 (Phenomenex Luna C18 column, 4.6×50 mmeluting with 10-90% MeCN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4mL/min, monitoring at 220 nm).

To a solution of(R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(12 mg, 0.019 mmol) in MeCN (115 μL) at rt was added K₂CO₃ (3.2 mg,0.023 mmol) followed by MeI (1.5 μL, 0.023 mmol). The reaction mixturewas heated to 80° C. overnight. The reaction mixture was quenched byaddition of H₂O and the aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were concentrated and the residue was dissolvedin MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18,eluting with MeCN/H₂O containing 0.1% TFA, monitoring at 220 nm) toprovide(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)urea(Example 260, 2 mg, 18% yield) as white solid. ¹H NMR (500 MHz, CDCl₃)ppm 7.17-7.08 (m, 5H), 6.99-6.85 (m, 5H), 6.67 (d, J=5Hz, 2H), 5.98-5.75(m, 1H), 4.23 (s, 3H), 3.82 (d, J=15 Hz, 1H), 3.68 (d, J=15 Hz, 1H),3.10-3.07 (m, 2H), 2.85-2.82 (m, 2H), 1.77-1.71 (m, 2H), 1.46-1.40 (m,2H), 1.32-1.26 (m, 2H); LC/MS: RT=3.218 min [M+H] 621.2 (Phenomenex LunaC18 column, 4.6×50 mm eluting with 10-90% MeCN/H₂O over 4 minutescontaining 0.1% NH₄OAc; 4 mL/min, monitoring at 220 nm).

Example 261

(R)-N-(1-(4-cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 56

To a solution of(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(2.44 g, 4.13 mmol), prepared as described in Procedure 3, 4, 5 and 6,in DMF (20 mL) were added zinc cyanide (970 mg, 8.27 mmol) and zinc dust(81 mg, 1.24 mmol). The reaction mixture was degassed with Ar and placedunder nitrogen. Palladiumbistributylphosphine (41 mg, 0.20 mmol) wasadded and the reaction mixture was heated at 60° C. for 16 h. Thereaction mixture was quenched with sat. sodium bicarbonate and extractedwith ethyl acetate. The combined organic extracts were dried overMg₂SO₄, filtered and concentrated to provideN-((R)-1-(4-cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white solid (2.08 g, 93% yield). LC/MS: RT=2.25 min [M+H] 537(Chromolith Performance 18e 4.6×100 mm column, 10-90% CH₃OH/H₂O with0.1% TFA gradient over 2 min, 5 mL/min, monitoring at 220 nm).

Following Procedure 6 and 7,(R)-N-(1-(4-cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 261) was prepared as a white powder (380 mg, 89% yield). LC/MS:RT=2.33 min [M+H] 623 (Chromolith Performance 18e 4.6×100 mm column,10-90% CH₃OH/H₂O with 0.1% TFA gradient over 2 min, 5 mL/min, monitoringat 220 nm); ¹H NMR (400 MHz, CDCl₃) ppm 7.91 (1H, d, J=6.60 Hz),7.81-7.86 (1H, m), 7.67 (2H, d, J=8.24 Hz), 7.38 (2H, d, J=8.25 Hz),7.24 (CHCl₃) 7.24-7.31 (2H, m), 7.18 (2H, t, J=7.42 Hz), 7.05 (1H, m),6.90 (2H, m), 6.64-6.75 (3H, m), 5.88 (1H, tt, J_(HH)=2.75 Hz, J_(HF)=53Hz), 3.90 (2H, s).

Example 262

(R)-methyl4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoateProcedure 57

(R)-N-(1-(4-Cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 261, 118 mg, 0.19 mmol) was dissolved in methanol (10 mL).Hydrogen chloride gas was bubbled into the solution for 5 min and thereaction mixture was stirred at 55° C. for 22 h. Then hydrogen chloridegas was bubbled to the mixture again for 4 min. After stirring foradditional 22 h, the reaction was quenched with sat. NaHCO₃ and themixture was extracted with ethyl acetate. The organic extracts weredried over MgSO₄, filtered and concentrated to yield a white solid. Theresulting solid was purified by ISCO flash chromatography (12 g silicagel; 0-50% ethyl acetate/hexane gradient over 12 min., 30 mL/min) toprovide (R)-methyl4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoate(Example 262) as a white solid (92 mg, 74% yield). LC/MS: RT=2.37 min[M+H] 656 (Chromolith Performance 18e 4.6×100 mm column, 10-90%CH₃OH/H₂O with 0.1% TFA gradient over 2 min, 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 8.02 (2H, d, J=8.25 Hz), 7.92 (1H, d,J=6.60 Hz), 7.77-7.88 (2H, m), 7.21-7.30 (3H, m), 7.24 (s, CHCl₃), 7.15(2H, t, J=7.42 Hz), 6.89-7.00 (3H, m), 6.64-6.72 (3H, m), 5.87 (1H, tt,J_(HH)=2.75 Hz, J_(HF)=53 Hz), 4.03 (1H, d, J=13.19 Hz), 3.93 (3H, s),3.86 (1H, d, J=13.19 Hz).

Example 263

(R)-N-(1-(4-(aminomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 58

To a solution of(R)-N-(1-(4-Cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 261, 59 mg, 0.095 mmol) in methanol (2 mL) was added cobaltchloride hexahydrate (45 mg, 0.19 mmol), followed by sodium borohydride(36 mg, 0.95 mmol). The reaction mixture was stirred for 13 h, thenquenched with HCl (1.0 M, 2 mL) and stirred for additional 1 h. Thereaction mixture was diluted with sat. ammonium hydroxide then extractedwith ethyl acetate. The organic extracts were dried over MgSO₄, filteredand concentrated to yield a white solid. The resulting solid waspurified by preparative HPLC (YMC ODS-A s-5 20×100 mm column; 50-90%MeOH/H₂O with 0.1% TFA gradient over 10 min., 20 mL/min, monitoring at220 nm) to provide(R)-N-(1-(4-(aminomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-(trifluoromethyl)benzamide(Example 263) as a white solid (39 mg, 56% yield). LC/MS: RT=1.65 min[M+H] 627 (Chromolith Performance 18e 4.6×100 mm column, 10-90%CH₃OH/H₂O with 0.1% TFA gradient over 2 min, 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 8.06 (2H, br s), 7.81 (1H, d, J=6.05Hz), 7.67-7.77 (1H, m), 7.34 (2H, d, J=7.70 Hz), 7.18-7.27 (3H, m), 7.24(CHCl₃, s), 7.13 (2H, t, J=7.42 Hz), 6.90 (1H, d, J=8.25 Hz), 6.72-6.81(3H, m), 6.66 (2H, d, J=7.15 Hz), 5.88 (1H, tt, J_(HH)=2.75 Hz,J_(HF)=53 Hz), 4.01 (2H, br s), 3.77-(2H, dd, J=29.1 Hz, J=13.2 Hz).

Example 264

(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide Procedure 59a

To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene,prepared as described in Procedure 3, (1.00 g, 3.44 mmol) in diethylether in (10 mL) at −72° C. was added 2.5 M n-BuLi (1.37 mL, 3.44 mmol)dropwise. Upon completion of addition, the reaction mixture was stirredfor 15 minutes at −72° C., then 4-fluoro-3-methoxybenzaldehyde (0.53 g,3.44 mmol) was added while the reaction mixture temperature wasmaintained below −52° C. The reaction mixture was stirred for 3 h at−72° C. The reaction mixture was quenched by the addition of 1N HCl andthe aqueous portion was extracted with EtOAc (2×). The combined organiclayers were washed with sat. NaCl, dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified by ISCO using agradient of 0-50% EtOAc/hexane as eluent to yield(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(0.83 g, 66% yield). HPLC: RT=3.85 min (Phenomenex Luna C18 5μ column,eluting with 10-90% aqueous methanol containing 0.1% phosphoric acidover a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); ¹HNMR (CDCl₃): 7.05-6.8 (m, 6H), 5.87 (tt, J=2.8, 52.9 Hz), 5.75 (s, 1H),3.85 (s, 3H).

Procedure 59b

To a solution of(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(0.58 g, 1.57 mmol) in CH₂Cl₂ (5 mL) was added activated manganesedioxide (0.80 g, 7.86 mmol). The reaction mixture was stirred overnightat rt. Additional manganese dioxide (0.80 g, 7.86 mmol) was added andthe reaction stirred at rt for another overnight. The reaction mixturewas diluted with CH₂Cl₂ and filtered through celite and the solid waswashed with CH₂Cl₂. The filtrate was concentrated under reduced pressureto yield(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone(0.56 g, 98% yield). HPLC: RT=4.048 minutes (Phenomenex Luna C18 5μcolumn, eluting with 10-90% aqueous methanol containing 0.1% phosphoricacid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220nm); LCMS: [M+H] 365.2 (Phenomenex Luna C18 5μ column, eluting with10-90% aqueous methanol containing 0.1% TFA over a 2 minute gradient,flow rate 5 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃):7.5-7.1 (m, 6H), 5.92 (tt, J=2.2, 53.6 Hz, 1H), 3.93 (s, 3H).

(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidemay also be prepared by the methods described in Procedure 59c, 59d, 59eand 59f.

Procedure 59c

To a solution of 4-fluoro-3-methoxybenzaldehyde (25 g, 162 mmol) in THF(150 mL) was added a solution of benzyl magnesium chloride (2 M solutionin THF, 122 mL, 243 mmol) in THF (50 mL). The reaction mixture washeated at 50° C. for 2 h. The reaction mixture was allowed to cool to rtand quenched by addition of sat. NH₄Cl. The reaction mixture wasextracted with EtOAc (3×) and the combined organic layers were washedwith sat. NaCl, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂, eluting with 0-40% EtOAc/hexane) to yield1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol as a yellow oil (24 g, 60%yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.27-7.32 (m, 2H), 7.21-7.27 (m,1H), 7.16 (d, J=7 Hz, 2H), 7.01 (dd, J=11, 8 Hz, 1H), 6.92 (dd, J=8, 2Hz, 1H), 6.82 (ddd, J=8, 4, 1 Hz, 1H), 4.80-4.88 (m, 1H), 4.66 (d,J=6Hz, 1H), 3.84 (s, 3H), 2.91-3.04 (m, 2H).

Procedure 59d

To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol (23.7 g,40.6 mmol) in acetone (240 mL) was added Jones reagent (64 mL) at rt.The reaction mixture was stirred overnight, quenched by the addition ofisopropanol and diluted with EtOAc. The organic portion was washed with1 N HCl (2×), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield the 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (15g, 66% yield). LCMS: RT=3.250 min [M+H] 245.1 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% NH₄OAc; 4 mL/min, monitoring at 220 nm); ¹H NMR (500 MHz, CDCl₃) δppm 7.62 (dd, J=8, 1 Hz, 1H), 7.60-7.55 (m, 1H), 7.35-7.29 (m, 2H),7.26-7.23 (m, 3H), 7.10 (dd, J=10, 8 Hz, 1H), 4.24 (s, 2H), 3.89 (s,3H).

Procedure 59e

To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (13 g, 53mmol) dissolved in THF (266 mL) was added(R)-2-methylpropane-2-sulfinamide (7.8 g, 64 mmol) at rt, followed byTi(OEt)₄ (17 mL, 80 mmol). The reaction mixture was heated to reflux for48 h, then allowed to cool to rt. The reaction mixture was concentratedunder reduced pressure and the residue was diluted with Et₂O. H₂O wasadded and the solid was filtered and washed with Et₂O. The filtrate waswashed with H₂O, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂, eluting with 0-100% EtOAc/hexane) to yield(R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide(12 g, 67% yield). LCMS: RT=3.655 min [M+H] 348.2 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% NH₄OAc; 4 mL/min, monitoring at 220 nm); ¹H NMR (500 MHz, CDCl₃) δppm 7.60-7.53 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.15 (m, 5H), 7.03 (dd,J=11, 8 Hz, 1H), 4.75 (d, J=15 Hz, 1H), 4.54 (d, J=15 Hz, 1H), 3.84 (s,3H), 1.34 (s, 9H).

Procedure 59f

To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene(357 mg, 1.23 mmol) in toluene (1.5 mL) at −60° C. was added n-BuLi (2.5M in hexane, 352 mL, 0.88 mmol). The reaction mixture was stirred for1.5 h at −20° C. to −55° C. In a separate vial, to a −78° C. solution of(R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide(122 mg, 0.35 mmol) in toluene (1 mL) was added Al(CH₃)₃ (210 mL, 0.42mmol). The resulting solution was stirred for 10-15 min, then added tothe mixture of (3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)lithium.The combined reaction mixture was stirred at −55° C. overnight and thendiluted with EtOAc. The organic portion was washed with H₂O and theaqueous portion was extracted with EtOAc (3×). The combined organicportions were concentrated under reduced pressure and the residue waspurified by preparative HPLC (Phenomenex Luna AXIA 100A, C18, 5; 10%-90%ACN/H₂O containing 0.1% TFA, monitoring at 220 nm) to yield(R)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(83 mg, 42% yield). LCMS: RT=3.49 min [M+H] 560.1 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% NH₄OAc; 4 mL/min, monitoring at 220 nm); ¹H NMR (500 MHz, CDCl₃) δ7.21-7.12 (m, 3H), 7.08 (dd, J=11, 8 Hz, 1H), 7.00-6.94 (m, 1H),6.91-6.81 (m, 4H), 6.72-6.62 (m, 2H), 5.99-5.70 (m, 1H), 4.36 (s, 1H),3.96 (d, J=13 Hz, 1H), 3.77 (s, 3H), 3.55 (d, J=13 Hz, 1H), 1.21 (s,9H).

Procedure 59 g

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide,prepared as described in Procedure 3, 59a-f, 6 and 7, (2.8 g, 4.43 mmol)in CH₂Cl₂ (15 mL) was added BBr₃ (12 mL, 12 mmol). The resulting mixturewas stirred at room temperature for 2 h and quenched by addition of ice.The reaction mixture was diluted with EtOAc and washed with sat. NaHCO₃,sat. NaCl, dried over Na₂SO₄, filtered and concentrated to afford(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264)as clear oil (2.9 g, 100% yield). LCMS: RT=4.176 min [M+H] 632.2 (4 minPhenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).

Example 265

3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropylacetate Procedure 60

A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (6 mL,159 mmol) was heated at 60° C. for 3 h, then cooled to rt. An aliquot ofthe resulting solution (0.623 mL) was added to a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamineprepared as described in Procedure 3, 4, 5 and 6 (83 mg, 0.2 mmol) inDCE (1 mL). The reaction mixture was stirred at rt for 1.5 h, thenconcentrated under reduced pressure to yield a clear oil. The resultingoil was dissolved in DCM and purified by ISCO chromatography (12 g) with0-30% EtOAc in hexane to yield(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamideas white solid (72 mg, 81% yield). LCMS: RT=2.02 min [M−NHCOH] 409.1 (2min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂Oover 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). At0° C. to a solution of(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide(72 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43mmol) and POCl₃ (0.016 mL, 0.18 mmol). The reaction mixture was stirredat rt overnight, then diluted with EtOAc (15 mL). The organic layer waswashed with sat. NaHCO₃ and sat. NaCl, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified byISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzeneas a white solid (60 mg, 87% yield). LCMS: RT=2.10 min [M−NC] 409.1 (2min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂Oover 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹HNMR (400 MHz, CDCl₃) δ ppm 3.56-3.65 (m, 2H), 5.74-6.01 (m, 1H), 6.84(d, J=7.03 Hz, 2H), 6.94 (d, J=7.03 Hz, 3H), 7.04-7.10 (m, 2H),7.16-7.26 (m, 3H), 7.32 (dd, J=9.01, 5.05 Hz, 2H).

To a solution of 2-phenyloxirane (0.009 mL, 0.08 mmol) in THF (1.5 ml)was added LiOTf (12 mg, 0.08 mmol),(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene(30 mg, 0.07 mmol) and acetic acid (0.004 mL, 0.08 mmol) in succession.The reaction mixture was heated to reflux for 3 h. The reaction wasallowed to cool to rt and diluted with EtOAc (15 mL). The organic layerwas washed with sat. NaCl, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting crude mixture was purified bypreparative HPLC YMC ODS S5 30×100 mm column 30-100% MeOH (90% in water,0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detectionat 220 nm to yield3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropylacetate (Example 265) as a white solid (26 mg, yield 62%, 1:1 RR:RSdiastereomer mixture). LCMS: RT=2.19 min [M+H] 616.3 (2 min PhenomenexLuna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.27 min,Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.96 (d, J=4.95 Hz, 3H), 3.01 (ddd,J=14.30, 6.87, 3.02 Hz, 1H), 3.14 (td, J=8.94, 5.22 Hz, 1H), 3.523 (d,J=13.2 Hz, 0.5H), 3.62 (m, 0.5H), 3.72 (m, 0.5H), 3.82 (d, J=13.2 Hz,0.5H), 5.30-5.34 (m, 1H), 5.74-5.97 (m, 1H), 6.46-6.53 (m, 2H), 6.60 (d,J=10.45 Hz, 1H), 6.67-6.72 (m, 1H), 6.80-7.31 (m, 13H).

Example 266

(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamideProcedure 61

To a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate (426 mg,2.15 mmol) in MeOH (15 mL) was added a solution of LiOH in H₂O (2 N,5.35 mL, 10.75 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction was concentrated and the resultingmixture was diluted with DCM and washed with 3 N HCl. The aqueous layerwas extracted twice with DCM. The combined organic layers were driedover MgSO₄, filtered and concentrated to yield4,4,4-trifluoro-2,2-dimethylbutanoic acid as a colorless oil (370 mg,100% yield). ¹H NMR (400 MHz, CDCl₃) ppm 1.35 (s, 6H), 2.48 (ABqt, J=12Hz, 2H).

To a solution of 4,4,4-trifluoro-2,2-dimethylbutanoic acid (30 mg, 0.176mmol) in DCE (1 mL) was added SOCl₂ (21 mg, 0.176 mmol) and theresulting mixture was refluxed for 2 h. After cooling to roomtemperature, TEA was added (82 uL, 0.59 mmol), followed by the additionof(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine,prepared as described in Procedure 3, 4, 5 and 6, (25 mg, 0.059 mmol).The reaction mixture was heated to reflux overnight, concentrated andthe residue was purified by preparative HPLC (Axia column, 30×100 mm, 40mL/min, 40-100% ACN/H₂O/0.1% TFA over 12 min) to give(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide(Example 266) as a brownish oil (8 mg, 24% yield). LCMS: RT=2.13 min[M+H] 578.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) ppm 1.28 (s, 6H), 2.21-2.51 (m, 2H), 3.77(ABqt, J=13 Hz, 2H), 5.83 (t, J=53 Hz, 1H), 6.37 (s, 1H), 6.65-6.74 (m,2H), 6.75-6.95 (m, 3H), 6.94-7.09 (m, 4H), 7.09-7.31 (m, 3H).

Example 267

N-(1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 62

To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene(5.0 g, 17 mmol) in ether (40 mL) at −78° C. was added a solution ofn-butyllithium (6.9 mL, 2.5 M, 17 mmol). The reaction mixture wasstirred for 15 minutes and was added a solution of3-bromo-4-fluorobenzaldehyde (3.5 g, 17 mmol) in ether (10 mL). Thereaction was stirred at −78° C. for 2 h, then quenched with sat. NH₄Cland warmed to room temperature. The ether layer was separated and driedover magnesium sulfate, filtered and concentrated to yield(3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanolas an amber oil (6.5 g, 92% yield). The product was used in the nextstep without further purification. To a solution of(3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(29.5 g, 71.3 mmol) in dichloromethane (600 mL) was added MnO₂ (30 g,345 mmol). The reaction mixture was stirred for 6 h, then another 30 gof MnO₂ was added and the reaction continued to stir overnight. The MnO₂addition was repeated twice and the reaction was stirred for a total of48 h when the reaction was complete. The suspension was filtered througha pad of celite, the filtrate vas concentrated and the residue waspurified by ISCO flash chromatography to yield(3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneas a yellow oil (60% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.06 (1H, d,J=6.59 Hz), 7.76 (1H, ddd, J=6.48, 4.50, 2.20 Hz), 7.38-7.44 (2H, m),7.21-7.29 (2H, m), 6.09-5.83 (1H, t).

Alternatively, the following conditions may be used to oxidize3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanolto(3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone:To a solution of(3-bromo-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(3.6 g, 8.67 mmol) in CH₂Cl₂ (53.0 ml) was added pyridinium dichromate(4.89 g, 13.01 mmol), and activated molecular sieves (8.67 g, ˜1g/mmole). The resulting slurry was stirred at room temperature for 2 h.Celite (5 g) was added to the reaction mixture and the slurry stirredfor 15 minutes then filtered. The filtrate was concentrated to in vacuo.The residue was dissolved in 20% EtOAc in Heptanes filtered through a50m Isolute SPE filtration column (part #120-1028F) over Na₂SO₄ to givea clear pale yellow solution. The solvents were removed in vacuo to agive a yellow liquid which was purified by ISCO silica gelchromatography (80 g, 60 mL/min observation at 254 nm elution withheptane:EtOAc).

N-(1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidewas prepared as described in Procedure 5 and 6. The diastereomer mixtureofN-(1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidewas separated by chiral preparative HPLC (chiralpak AD 20μ column, 5×50cm, eluting with 60% IPA/Heptane with flow rate 50 mL/min).(R)-N-((S)-1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(0.224 g, 18% yield) was eluted at a retention time of 19 min. LCMS:RT=2.23 min, Purity 71% [M+H] 555.3 (2 min Chromolith Performance RP4.6×100 mm column, eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA with flow rate 5 mL/min, monitoring at 220 nm);Analytical Chiral HPLC: RT=4.01 min (Chiralpak AD 10 column 4.6×250 mm,isocratic elution with 50% IPA/Heptane with flow rate 1 mL/min,monitoring at 254 nm); ¹H NMR (400 MHz, CDCl₃) ppm 1.23 (s, 9H), 3.55(d, J=12.3 Hz, 1H), 3.97 (d, J=12.3 Hz, 1H), 5.89 (t, J=53.17 Hz, 1H)6.85 (d, J=6.6 Hz, 2H), 6.94 (s, 1H), 7.00 (d, J=8.3 Hz, 1H), 7.12-7.22(m, 4H), 7.24-7.29 (m, 2H), 7.37 (d, J=4.8 Hz, 1H).(R)-N-((R)-1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(0.266 g, 22% yield) was eluted at a retention time of 41 min. LCMS:RT=2.23 min, purity 84% [M+H] 555.3 (2 min Chromolith Performance RP4.6×100 mm column, eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA with flow rate 5 mL/min, monitoring at 220 nm);Analytical Chiral HPLC: RT=10.09 min (Chiralpak AD 10 column 4.6×250 mm,isocratic elution with 50% IPA/Heptane with flow rate 1 mL/min,monitoring at 254 nm); ¹H NMR (400 MHz, CDCl₃) ppm 1.18-1.25 (m, 9H),3.59 (d, J=12.3 Hz, 1H), 3.99 (d, J=12.3 Hz, 1H), 4.30 (s, 1H), 5.87 (t,1H) 6.64-6.71 (m, 2H), 6.90 (d, J=7.0 Hz, 3H), 7.15-7.22 (m, 3H),7.23-7.29 (m, 2H), 7.64-7.71 (m, 2H).

(R)-N-(1-(3-cyano-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 267) was prepared as described in Procedure 6 and 7. LCMS:RT=2.342 min [M+H] 641.3 (2 min Chromolith Performance RP 4.6×100 mmcolumn eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFAwith flow rate 5 mL/min. monitoring at 220 nm); HPLC: RT=4.358 min,Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% PPA with flow rate 4 mL/min,monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 3.76-3.81 (m, 2H),5.89 (t, J=53.1 Hz, 1H), 6.68-6.73 (m, 3H), 6.81-6.85 (m, 2H), 6.99 (d,J=8.3 Hz, 1H), 7.19-7.30 (m, 6H), 7.54-7.58 (m, 2H), 7.82-7.86 (m, 1H),7.92 (d, J=6.6 Hz, 1H).

Example 268

(R)-tert-butyl2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzylcarbamateProcedure 63

A mixture of(3-bromo-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone,prepared as described in Procedure 3 and 62, (2.0 g, 4.84 mmol), zinccyanide (568 mg, 4.84 mmol) and tetrakis(triphenyphoshine)palladium (559mg, 0.48 mmol) in DMF was heated at 175° C. under microwave irradiationfor 10 minutes. The reaction mixture was allowed to cool to roomtemperature, poured into H₂O and the aqueous layer was extracted withEtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by ISCO chromatography (12g column, 0-20% EtOAc/hexane) to yield2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrileas a colorless oil (1.5 g, 86% yield). ¹H NMR (400 MHz, CDC₃) δ ppm 8.11(m, 2H), 7.41 (m, 3H), 7.27 (m, 1H), 5.97 (m, 1H).

To a solution of2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile(1.30 g, 3.62 mmol), BOC₂O (1.68 mL, 7.24 mmol) and Nickel (II) chloride(0.47 g, 3.62 mmol) in MeOH at 0° C. was added sodium borohydride (0.96g, 25.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutesand then at room temperature for 6 h. The reaction mixture was filteredthrough celite and the filtrate was concentrated. The residue wasdiluted with EtOAc and the solution was washed with sat. NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and concentrated to yieldtert-butyl2-fluoro-5-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(hydroxy)methyl)benzylcarbamateas a clear, colorless oil (1.43 g, 85% yield). This product was used inthe next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 7.32 (m, 1H), 7.22 (m, 1H), 7.03 (m, 3H),), 6.87 (d, J=8.84 Hz, 1H),5.90 (m, 2H), 4.98 (br. s., 1H), 4.31 (d, J=5.05 Hz, 2H).

To a solution of tert-butyl2-fluoro-5-(hydroxy(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethyl)phenyl)methyl)benzylcarbamate(1.43 g, 2.77 mmol) in CH₂Cl₂ (25 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.77 g,4.16 mmol) at rt. Water (0.2 mL) in CH₂Cl₂ (1 mL) was then added to thereaction mixture and the resulting solution was stirred at rt for 3 h,then the solid was filtered and the filtrate was concentrated. Theresidue was purified by ISCO chromatography (12 g column, 0-30%EtOAc/hexane) to yield tert-butyl2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl) as a clear,colorless oil (915 mg, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85(d, J=7.07 Hz, 1H), 7.73 (m, 1H), 7.40 (m, 2H), 7.18 (m, 2H), 7.00 (m,1H), 5.96 (m, 1H), 1.41 (m, 9H).

Following Procedure 5 and 6, tert-butyl5-((1R)-1-(1,1-dimethylethylsulfinamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-fluorobenzylcarbamatewas prepared and isolated by ISCO chromatography (40 g column, elutingwith 0-40% EtOAc/hexane). Following Procedure 6,(R)-1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-2-phenylethanaminewas prepared as a colorless oil (214 mg, 40% yield). ¹H NMR (500 MHz,CDCl₃) δ ppm 7.32 (d, J=5.50 Hz, 1H), 7.19 (m, 4H), 6.98 (br. s., 3H),6.84 (d, J=7.70 Hz, 1H), 6.72 (d, J=6.60 Hz, 2H), 5.86 (t, J=53.06 Hz,1H), 3.85 (br. s., 2H), 3.50 (m, 2H).

To a solution of(R)-1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine(229 mg, 0.50 mmol) at 0° C. in CH₂Cl₂ (5 mL) was added DIEA (0.11 mL,0.61 mmol) and (Boc)₂O (0.12 mL, 0.50 mmol). The reaction mixture wasstirred at 0° C. for 1.5 h and was then poured into sat. NH₄Cl and theaqueous layer was extracted with EtOAc. The organic phase was dried overNa₂SO₄, filtered and concentrated. The resulting residue was purified byISCO column chromatography (12 g, 0-30% EtOAc/hexane) to yield(R)-tert-butyl5-(1-amino-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-fluorobenzylcarbamateas a white foam (202 mg, 72% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.49(s, 2H), 7.34 (m, 1H), 7.17 (m, 4H), 6.97 (m, 3H), 6.83 (d, J=8.84 Hz,1H), 6.73 (d, J=6.32 Hz, 2H), 5.86 (m, 1H), 4.86 (br. s., 1H), 4.31 (d,J=4.55 Hz, 2H), 3.49 (s, 2H), 1.42 (s, 9H).

(R)-tert-Butyl2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzylcarbamate(Example 268) was prepared as a colorless oil (220 mg, 91% yield) usingthe method described in Procedure 7. LCMS: RT=3.47 min [M+H-17]538(Phemonenex Luna C18, 50×4.6 mm, 4 min gradient, eluting with 105-90%MeOH/H₂O containing 0.1% TFA, monitoring at 220 nm); ¹H NMR (400 MHz,CDCl₃) δ ppm 7.97 (d, J=5.31 Hz, 1H), 7.84 (br. s., 1H), 7.24 (m, 2H),7.15 (m, 3H), 6.96 (m, 5H), 6.71 (m, 3H), 5.86 (m, 1H), 4.84 (br. s.,1H), 4.27 (t, J=6.19 Hz, 2H), 4.02 (m, 1H), 3.79 (d, J=13.14 Hz, 1H),1.37 (s, 9H).

Example 269

(R)-N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidehydrochloride Procedure 64

To a solution of (R)-tert-butyl5-(1-amino-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-fluorobenzylcarbamate(222 mg, 0.30 mmol) in DCM (5 ml) at rt was added 2 M HCl in diethylether (1.49 mL, 1.49 mmol). The reaction mixture was stirred for 2 h,then concentrated under reduced pressure to yield(R)-N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidehydrochloride (Example 269) as a white foam (216 mg, 100%). ¹H NMR (400MHz, CDCl₃) δ ppm 7.95 (m, 1H), 7.84 (m, 1H), 7.19 (m, 4H), 6.91 (m,3H), 6.70 (d, J=7.07 Hz, 2H), 5.88 (m, 1H), 4.24 (t, J=5.31 Hz, 1H),4.06 (m, 1H), 3.79 (m, 2H).

Example 270

(R)-N-(1-(3-(acetamidomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 65

To a solution of(R)-N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidehydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt wasadded pyridine (7.8 μL, 0.1 mmol) followed by acetic anhydride (4.6 μL,0.05 mmol). The reaction mixture was stirred at rt for 1 h, then pouredinto 1N HCl and the aqueous layer was extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The resultingresidue was purified by ISCO column chromatography (4 g, 0-50%EtOAc/hexane) to yield(R)-N-(1-(3-(acetamidomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 270) as a white foam (21 mg, 100%). ¹H NMR (400 MHz, CDCl₃) δppm 7.98 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (dt, J=8.53, 2.18 Hz, 1H), 7.25(m, 2H), 7.13 (m, 3H), 6.99 (m, 5H), 6.81 (s, 1H), 6.69 (m, 2H), 5.87(m, 2H), 4.38 (m, 2H), 4.04 (d, J=13.14 Hz, 1H), 3.75 (d, J=13.14 Hz,1H), 1.92 (s, 3H).

Example 271

(R)-4-fluoro-N-(1-(4-fluoro-3-(methylsulfonamidoethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 66

To a solution of(R)-N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidehydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt wasadded TEA (6.8 μL, 0.05 mmol) followed by methanesulfonyl chloride (3.4μL, 0.04 mmol). The reaction mixture was stirred at rt for 1 h and thenpoured into 1 N HCl. The aqueous layer was extracted with CH₂Cl₂ and thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by ISCO column chromatography (4g, 0-40% EtOAc/hexane) to yield(R)-4-fluoro-N-(1-(4-fluoro-3-(methylsulfonamidomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 271) as a clear, colorless film (12 mg, 41%). ¹H NMR (400 MHz,CDCl₃) 7.95 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (m, 1H), 7.22 (m, 7H), 7.07(t, J=8.97 Hz, 1H), 6.93 (m, 3H), 6.71 (m, 3H), 5.88 (m, 1H), 4.55 (t,J=6.32 Hz, 1H), 4.30 (t, J=5.81 Hz, 2H), 3.97 (m, 1H), 3.83 (m, 1H),2.81 (s, 3H).

Example 272

(R)-2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenylmethylcarbamate Procedure 67

A solution of(R)-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide,prepared as described in Example 264, (15 mg, 0.027 mmol),methylisocyanate (0.01 mL), and Et₃N (0.02 mL) in CH₂Cl₂ (0.3 mL) washeated at 80° C. under microwave irradiation for 10 min. After cooling,the reaction mixture was diluted with EtOAc and the organic layer waswashed with H₂O, sat. NaCl, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by ISCO flash chromatography(silica gel, hexanes/EtOAc) to yield(R)-2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)-benzamido)-ethyl)phenylmethylcarbamate (Example 272, 11 mg, yield: 61%). LCMS: RT=2.13 min[M+H] 623.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm).

Example 273

(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide Procedure 68

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264,2.70 g, 4.27 mmol) in DMF (6 mL) was added K₂CO₃ (1.47 g, 10.69 mmol),followed by isopropyl iodide (0.64 mL, 6.40 mmol). The reaction mixturewas stirred at 60° C. for 16 h. The reaction mixture was filtered andthe solid was washed with EtOAc. The filtrate was washed with H₂O, sat.NaCl, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by ISCO silica gel column using 0 to 50% EtOAc inhexane as eluting solvents to yield(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 273)as white powder (2.4 g, 83% yield). LCMS: RT=4.05 min [M+H] 674.1(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CD₃OD) δ ppm 7.95-8.00 (2H, m), 7.42-7.47 (1H, m), 7.19 (1H,t, J=7.47 Hz), 7.12 (3H, t, J=7.25 Hz), 6.99-7.07 (3H, m), 6.71-6.81(4H, m), 6.14-6.41 (1H, m), 4.26-4.32 (1H, m, J=6.15, 6.15, 6.15, 6.15Hz), 4.12 (1H, d, J=13.18 Hz), 3.85 (1H, d, J=12.74 Hz), 1.23 (3H, d,J=6.15 Hz), 1.17 (3H, d, J=6.15 Hz).

Example 274

(R)-N-(1-(3-(1-amino-2-methyl-1-oxopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 69

At 0° C. to a solution of(R)-2-(2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenoxy)-2-methylpropanoicacid, prepared as described in Procedure 68 and 23, (60 mg, 0.092 mmol,yield 91%) in CH₂Cl₂ was added DMF (1 drop), followed by the addition of(COCl)₂ (0.02 mL). The reaction mixture was stirred at 0° C. for 30 min,then concentrated and dried in vacuo. The resulting residue wasdissolved in THF (1 mL) and cooled to 0° C. followed by the addition ofconcentrated NH₄OH (3 mL). The resulting mixture was stirred at rt for 1h, then concentrated under reduced pressure. The residue was dilutedwith CH₂Cl₂ and the organic layer was washed with H₂O, saturated NaCl,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (silica gel, hexanes/EtOAc) to give pure(R)-N-(1-(3-(1-amino-2-methyl-1-oxopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 274, 40 mg, yield: 67%). LCMS: RT=2.15 min [M+H] 651.2(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

Example 275

(R)-N-(1-(3-(2-cyanopropane-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 70

To a solution of(R)-N-(1-(3-(1-amino-2-methyl-1-oxopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 274, 30 mg, 0.046 mmol) in DMF (1 mL) at room temperature wasadded thionyl chloride (3 drops). The reaction mixture was stirred for40 min and diluted with H₂O and EtOAc. The organic layer was washed withH₂O, saturated NaHCO₃, H₂O and saturated NaCl, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (silica gel, hexanes/EtOAc) to givepure(R)-N-(1-(3-(2-cyanopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 275, 16 mg, yield: 55%). LCMS: RT=2.21 min [M+H] 633.3(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

Example 276

(2S,4R)-4-fluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-1-(4-fluorophenyl)-2-phenylethyl)pyrrolidine-2-carboxamideProcedure 71

To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(42 mg, 0.1 mmol), prepared as described in Procedure 3, 4, 5 and 6, and(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid(23 mg, 0.1 mmol) in CH₂Cl₂ (1 mL) was added EDCI (25 mg, 0.1 mmol) andDMAP (16 mg, 0.1 mmol). The reaction mixture was stirred overnight andconcentrated to dryness under a stream of argon. The resulting residuewas dissolved in MeOH and purified by preparative HPLC (Phenoma LunaAXIA 10A, C18, eluting with 10-90% MeCN/H₂O containing 0.1% TFA,monitoring at 220 nm) to provide (2S,4R)-tert-butyl4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate(40 mg, 64% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.30(s, 1H), 7.13-7.03 (m, 5H), 6.95-6.90 (m, 2H), 6.80-6.78 (m, 2H), 6.70(bs, 1H), 6.51-6.47 (m, 2H), 5.88-5.67 (m, 1H, —CF₂H), 5.10 (app d, J=50Hz, 1H, —CFH), 4.48-4.45 (m, 1H), 3.89-3.78 (m, 2H), 3.70 (d, J=10 Hz,1H0, 3.29-3.18 (m, 1H), 2.79-2.55 (m, 2H), 2.25-2.11 (m, 1H), 1.32 (s,9H); LC/MS: RT=3.746 min [M+H] 641.2 Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeCN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4mL/min, monitoring at 220 nm.

(2S,4R)-tert-butyl4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate(18 mg, 0.03 mmol) was dissolved in a solution of CH₂Cl₂ (1 mL)/TFA (1mL) at rt. The reaction mixture was stirred overnight and concentratedto dryness under a stream of argon. The resulting residue was dissolvedin MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18,eluting with 10%-90% MeCN/H₂O containing 0.1% TFA, monitoring at 220 nm)to provide(2S,4R)-4-fluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-1-(4-fluorophenyl)-2-phenylethyl)pyrrolidine-2-carboxamide(Example 276) as a white solid (13 mg, 83% yield). ¹H NMR (500 MHz,MeOH-d₄) δ ppm 7.22-7.13 (m, 7H), 7.07-6.96 (m, 7H), 6.68 (d, J=5Hz,2H), 6.40-6.18 (m, 1H, —CF₂H), 5.43 (app d, J=50 Hz, 1H, —CFH),4.55-4.51 (m, 1H), 4.01 (d, J=10 Hz, 1H), 3.92 (d, J=15 Hz, 1H),3.65-3.49 (m, 2H), 2.72-2.64 (m, 1H), 2.10-1.96 (m, 1H); LC/MS: RT=3.310min [M+H] 541.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeCN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min,monitoring at 220 nm).

Example 277

3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoicacid Procedure 72

At 0° C. to a solution of bis(3-(trifluoromethoxy)phenyl)methanone (3 g,8.6 mmol), prepared as described in Procedure 11, in DME (60 mL) wasadded 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.3 g, 17.1 mmol) andtBuOK (25.7 mL, 1.0 M solution in tBuOH, 25.7 mmol). The reactionmixture was allowed to warm to rt and stirred for 18 h. H₂O (100 mL) wasadded to the reaction mixture and the aqueous layer was extracted withDCM (3×100 mL). The combined organic layers were washed with sat. NaCl(50 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by ISCO chromatography (150 g) usinghexane/EtOAc (0-5% over 30 min, 5-20% over 20 min) to give2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile as a yellow oil at aretention time of 46 min (1.4 g, 45% yield). HPLC: RT=4.13 min, Purity100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂Oover 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm).NMR: 400 MHz ¹H (CDCL₃) 7.45 ppm, 2H, t, J=8.13 Hz; 7.30 ppm, 2H, d,J=7.91 Hz; 7.23 ppm, 2H, d, J=9.23 Hz; 7.17 ppm, 2H, s; 5.17 ppm, 1H, s.

Procedure 73

To a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (1.0 g,2.8 mmol) in AcOH (15 mL) was added 60% H₂SO₄ (aq) (10 mL) and thereaction mixture was heated at 100° C. for 10 h. The reaction mixturewas allowed to cool to rt and extracted with toluene (2×25 mL). Thecombined organic portions were washed with H₂O (25 mL) and sat. NaCl (25mL), then extracted with 0.5 N NaOH (50 mL and 10 mL). The combinedbasic extracts were made acidic using concentrated HCl then extractedwith toluene (2×25 mL). The combined organic extracts were dried overMgSO₄, filtered and concentrated under reduced pressure to give2,2-bis(3-(trifluoromethoxy)phenyl)acetic acid (700 mg, 67% yield) as apale tan oil. LCMS: RT=1.99 min [M+H] 381.1 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCL₃) δ ppm5.05 (s, 1H), 7.14-7.19 (m, 4H), 7.25 (d, J=7.47 Hz, 2H), 7.37 (t,J=7.69 Hz, 2H).

Procedure 74

To a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetic acid (198 mg,0.52 mmol) in THF (3.5 mL) at −15° C. was added dropwise a 1.6 Msolution of nBuLi in hexanes (0.65 mL, 1.04 mmol). The reaction mixturewas stirred for 45 min. The solution was cooled to −40° C. and asolution of benzylbromide (130 mg, 0.52 mmol) in THF (0.6 mL) was addeddropwise. The ice-bath was removed and the reaction mixture was allowedto warm up to rt. The reaction was quenched by addition of sat. NH₄Cl (5mL) and extracted with Et₂O (3×5 mL). The combined organic portions weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica chromatography, eluting with 30%EtOAc/hexane containing 1% AcOH to give3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (232mg, 81% yield) as a clear colorless oil. LCMS: RT=1.93 min [M+H] 549.0(2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 3.62 (s, 2H), 6.53 (d, J=8.35 Hz,2H), 7.04 (s, 2H), 7.10 (d, J=7.91 Hz, 2H), 7.13-7.19 (m, 4H), 7.30 (t,J=8.13 Hz, 2H).

Procedure 75

To a solution of3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (224mg, 0.41 mmol) in dioxane (5 mL) was added 4 A molecular sieves (appx100 mg), triethylamine (0.068 mL, 0.49 mmol) and diphenylphosphorylazide (0.11 mL, 0.49 mmol) and the reaction mixture was stirred for 45minutes. 2-(Trimethylsilyl)ethanol (0.176 mL, 1.23 mmol) was added andthe reaction mixture was heated at reflux for 1 h. The reaction mixturewas allowed to cool to rt and concentrated under reduced pressure. Theresidue was diluted with Et₂O (10 mL) and washed with sat. NH₄Cl (5 mL),sat. NaHCO₃ (5 mL) and sat. NaCl (5 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was diluted with THF (5 mL) and cooled in an ice-bath, then a 1Msolution of tetrabutylammonium fluoride in THF (0.80 mL, 0.80 mmol) wasadded dropwise. The reaction mixture was allowed to warm to rt andstirred for 3 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL) andwashed with H₂O (5 mL) and sat. NaCl (5 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified on ISCO silica chromatography withelution at 0 to 50% EtOAc/hexane to give2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (78 mg,37% yield) as a clear colorless oil. LCMS: RT=1.87 min [M−NH₂] 505.0 (2min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂Oover 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm);NMR: 400 MHz ¹H (CDCl₃) δ ppm 1.68 (bs, 2H), 3.46 (s, 2H), 6.57 (d,J=8.35 Hz, 2H), 7.10 (d, J=8.35 Hz, 2H), 7.18 (s, 2H), 7.21-7.26 (m,4H), 7.32 (t, J=8.13 Hz, 2H).

Procedure 76

To a solution of2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (26 mg,0.050 mmol) in THF (0.5 mL) was added a 0.5 M solution of3-ethoxy-3-oxopropylzinc bromide in THF (0.18 mL, 0.090 mmol) followedby tetrakis(triphenylphosphine)palladium(0) (3 mg, 5 mol %). Thereaction mixture was heated at 130° C. under microwave irradiation for0.5 h. The reaction mixture was filtered through silica gel and elutedwith THF. The solvents were removed under reduced pressure and theresidue was dissolved into CH₂Cl₂ (0.5 mL) then triethylamine (0.020 mL,0.15 mmol) was added followed by4-fluoro-3-(trifluoromethyl)benzoylchloride (0.020 mL, 0.13 mmol). Thereaction mixture was stirred at rt for 3 h then diluted with Et₂O (10mL) and the organic layer was washed with sat. NH₄Cl (2 mL), sat. NaHCO₃(2 mL) and sat. NaCl (2 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep TLC plate, eluting with 20% EtOAc/hexane to give ethyl3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoate(11 mg, 31% yield) as a clear, colorless oil. LCMS: RT=2.26 min [M+H]731.93 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm).

To a solution of ethyl3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoate(11 mg, 0.015 mmol) in THF (0.75 mL) was added 1 N LiOH (0.15 mL) andmethanol (0.30 mL). The reaction mixture was heated at 50° C. for 0.5 h.The solvents were removed under a stream of nitrogen then 1 N HCl (2 mL)was added to the residue and the mixture was extracted with CH₂Cl₂ (2×5mL). The combined organics were dried over Na₂SO₄, filtered and thevolatiles removed. The resulting residue was purified on ISCO silica geleluting with 0 to 10% MeOH/CH₂Cl₂ to give3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoicacid (Example 277) as a clear, colorless oil (9 mg, 85% yield). LCMS:RT=2.18 min [M+H] 704.1 (2 min Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 2.55 (t,J=7.69 Hz, 2H), 2.82 (t, J=7.69 Hz, 2H), 3.83 (s, 2H), 6.54 (d, J=8.35Hz, 2H), 6.60 (s, 1H), 6.93 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.08-7.14(m, 4H), 7.17-7.23 (m, 1H), 7.28-7.33 (m, 2H), 7.73-7.77 (m, 1H),7.83-7.86 (m, 1H).

Example 278

1-(2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 77

To a solution of3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (260mg, 0.47 mmol) in toluene (10 mL) was added diphenylphosphoryl azide(0.409 mL, 1.9 mmol) followed by triethylamine (0.264 mL, 1.9 mmol). Thereaction mixture was heated at reflux for 1 h, then trifluoroethylaminewas added and the reaction mixture was heated at reflux for another 1 h.The reaction mixture was allowed to cool to rt and diluted with EtOAc(30 mL) and washed successively with sat. NH₄Cl (10 mL), sat. NaHCO₃ (10mL) and sat. NaCl (20 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified on a ISCO silica gel column (12 g) with elution at 0 to 20%EtOAc/hexane over 20 min, then further purified by preparative HPLC YMCODS S5 30×100 mm column 40-100% MeOH/H₂O (90% in water, 0.1% TFA)gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nmto yield1-(2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea(Example 278) as a white solid (200 mg, yield 65%). LCMS: RT=2.24 min[M+H] 645.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm); HPLC: RT=4.476 min, Purity 100% (Phenomenex Luna C18 column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2%PPA; 4 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm3.68-3.77 (m, 2H), 3.81 (s, 2H), 4.80 (t, J=6.15 Hz, 1H), 5.15 (s, 1H),6.52 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.09-7.17 (m, 4H), 7.23-7.27 (m,3H), 7.34 (t, J=7.91 Hz, 2H).

Example 279

1-(2-(pyrimidin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 78

To a solution of 2-methylpyrimidine (2.0 g, 21.3 mmol) in CCl₄ (80 mL)was added benzoyl peroxide (80 mg, 0.33 mmol). The reaction mixture washeated to reflux, then NBS (4.5 g, 25.56 mmol) was added in portionsover 3.5 h. Reflux was maintained for 18 h and the reaction mixture wasallowed to cool to rt, filtered through a celite pad and the celite wasrinsed with ether (200 mL). The organic layer was concentrated and theresidue was purified by ISCO chromatography (120 g column) usinghexane/EtOAc (0-80% over 30 min) to give 2-(bromomethyl)pyrimidine as ayellow oil at a retention time of 18 min (412 mg, 11% yield). NMR: 400MHz ¹H (CDCl₃) 8.76 ppm, 2H, d, J=5.27 Hz; 7.23 ppm, 1H, m; 4.62 ppm,2H, d, J=2.20 Hz.

At −15° C. to a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)aceticacid prepared as described in Procedure 73 (607 mg, 1.6 mmol) in THF (6mL) was added nBuLi (1.6 mL, 2M in hexane, 3.2 mmol). The mixture wasstirred at −15° C. for 45 min. 2-(Bromomethyl)pyrimidine (412 mg, crude)in THF (1 mL) was added and the reaction mixture was allowed to warm tort and stirred for 18 h, then quenched with saturated NH₄Cl. The aqueouslayer was extracted with EtOAc (3×50 mL). The combined organic layer wasdried over MgSO₄, filtered and concentrated to give3-(pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid asa yellow solid (437 mg, 58% crude). This crude solid was carried ontothe next step without further purification.

To a mixture of3-(pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (20mg, 0.042 mmol) and diphenyl phosphoryl azide (70 mg, 0.254 mmol) intoluene (1.5 mL) was added TEA (88 μL, 0.63 mmol) dropwise and thereaction mixture was heated at 110° C. for 20 min.2,2,2-Trifluoroethanamine (7 μL, 0.084 mmol) was added and the reactionmixture was stirred at 110° C. for 1 h. The reaction mixture was allowedto cool to rt and diluted with EtOAc (25 mL). The organic layer waswashed with H₂O (25 mL), 1 N HCl (25 mL) and saturated NaHCO₃ (25 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (Shimadzu-YMC-Sunfire 5μcolumn, 30×100 mm eluting with 40-100% MeOH (90% in H₂O, 0.1% TFA)gradient over 10 min with flow rate 40 mL/min and UV detection at 220nm). The product that eluted at retention time of 9.42 min was isolatedas a clear oil, and further purified by Prep TLC (Uniplate, Silica GelGF, 20×20 cm, 1000 Microns) using Hexane/EtOAc (1/2) to yield1-(2-(pyrimidin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea(Example 279) as a white solid (4 mg, 16% yield). LCMS: RT=1.867 min[M+H] 568.87 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220nm); HPLC: RT=3.973 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 8.52 ppm, 2H, d,J=4.83 Hz; 7.98 ppm, 1H, s; 7.33 ppm, 5H, m; 7.23 ppm, 2H, s; 7.08 ppm,3H, t, J=5.05 Hz; 4.61 ppm, 1H, t, J=6.37 Hz; 3.85 ppm, 2H, s; 3.77 ppm,2H, ddd, J=15.71, 9.12, 9.01 Hz.

Example 280

N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 79

N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamidewas prepared as described in Procedure 11, 18, 6 and 7. LCMS: RT=4.04min [M+H] 581.16 (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm). A mixture ofN-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(70 mg, 0.12 mmol), TMSN₃ (0.025 ml. 1.6 eq) and TBAF.3H₂O (19 mg, 0.5eq) was heated in a sealed tube at 110° C. for 24 h. After allowing tocool to rt, the residue was dissolved in CH₂Cl₂, and purified by ISCOflash chromatography (silica gel, CH₂Cl₂/MeOH) to giveN-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 280, 54 mg, yield: 72%). LCMS: RT=3.91 min [M+H] 624.06, [M+Na]647.06 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm).

Example 281

4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 80

To a solution ofN-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(18 mg, 0.029 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at rt was added(diazomethyl)trimethylsilane (0.02 mL, 2.0 M solution). The resultingsolution was stirred at rt for 20 min. The solvents were evaporated andresulting residue was purified by ISCO flash chromatography (silica gel,hexane/EtOAc) to give4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 281, 11 mg, yield: 60%). LCMS: RT=4.06 min [M+H] 638.23, [M+Na]661.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm).

Example 282

2-(trimethylsilyl)ethyl2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate Procedure 81

To a solution of 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propanoicacid (0.055 g, 0.117 mmol) in 1,4-dioxane (2 mL) was added triethylamine(0.014 g, 20 μL, 0.14 mmol), 4 Å molecular sieves (0.05 g),diphenylphosphoryl azide (0.040 g, 31 μL, 0.14 mmol) andtrimethylsilylethanol (0.042 g, 50 μL, 0.35 mmol). The reaction mixturewas stirred for 1 h at rt, then heated at 75° C. for 1.5 h. The cooledreaction mixture was diluted with EtOAc and filtered through celite. Thefiltrate was concentrated under reduced pressure and purified by ISCOsilica gel chromatography using a gradient of 0-20% EtOAc/hexane aseluent to yield 2-(trimethylsilyl)ethyl2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate (Example 282)as a colorless band (0.037 g, 54% yield). HPLC: RT=4.828 min (PhenomenexLuna C18 5μ column 4.6×50 mm, eluting with 10-90% MeOH/H₂O containing0.1% PPA over a 4 minute gradient, monitoring at 220 nm). No molecularion was obtained. ¹H NMR (400 MHz, CDCl₃): 7.32 (t, J=8.1 Hz, 2H),7.18-7.11 (m, 7H), 6.99 (s, 2H), 6.65 (d, J=7.1 Hz, 2H), 5.35 (s, 1H),4.08 (t, J=8.8 Hz, 2H), 3.78 (s, 2H), 0.88 (br, 2H), 0.00 (s, 9H).

Example 283

2-methoxyethyl2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate Procedure 82

To a solution of 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine(20 mg, 0.045 mmol) in THF (6 mL) was added 1M K₂CO₃ (20 mg in 0.1 mL),followed by 2-methoxyethyl carbonochloridate (0.106 mL, 0.91 mmol). Theresulting mixture was stirred at rt for 16 h. The crude product waspurified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column elutingwith 10-90% ACN/H₂O over 10 minutes containing 0.1% TFA; 40 mL/min,monitoring at 220 nm) to afford 2-methoxyethyl2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate (Example 283)as white lyophillate (12 mg, 51% yield). LCMS: RT=4.19 min [M+H] 544.2(4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm.

Example 284

1-(2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-(trifluoromethyl)phenyl)thioureaProcedure 83

To a solution of bis(3-(trifluoromethoxy)phenyl)methanamine (20 mg,0.057 mmol) in CH₂Cl₂ (0.1 mL) was added1-isothiocyanato-3-(trifluoromethyl)benzene (35 mg, 0.17 mmol). Thereaction mixture was stirred at rt for 16 h. The reaction mixture wasconcentrated and the residue was purified by prep HPLC (phenomenex AXIALuna 75×30 mm, 5μ column eluting with 10-90% ACN/H₂O over 10 minutescontaining 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford1-(2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-(trifluoromethyl)phenyl)thiourea(Example 284) as white lyophillate (30 mg, 81%). LCMS: RT=4.51 min [M+H]645.14 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm).

Example 285

(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamideProcedure 84

At 0° C. under argon to a solution of4,4,4-trifluoro-3-(trifluoromethyl)crotonic acid (29 mg, 0.14 mmol) andTEA (25 μL, 0.18 mmol) in CHCl₃ (0.5 mL) was added isobutylchloroformate (18 μL, 0.14 mmol). The reaction mixture was stirred at 0°C. for 10 min. A solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine,prepared as described in Procedure 3, 4, 5 and 6, (50 mg, 0.12 mmol) inCHCl₃ (0.5 mL) was added and the reaction was stirred at rt for 18 h.The reaction mixture was concentrated and purified by preparative HPLCShimadzu-YMC Sunfire 5μ column, 30×100 mm eluting with 40-100% MeOH (90%in H₂O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UVdetection at 220 nm.(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(,1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide(Example 285) was eluted at a retention time of 11.11 min and wasisolated as a clear oil (63 mg, yield 73%). LCMS: RT=2.19 min [M+H]616.1 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=4.31 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.36 ppm, 2H, s;7.21 ppm, 3H, m; 7.09 ppm, 2H, m; 7.01 ppm, 2H, t, J=8.57 Hz; 6.91 ppm,3H, m; 6.64 ppm, 2H, d, J=7.03 Hz; 6.43 ppm, 1H, s; 3.94 ppm, 1H, d,J=13.18 Hz; 3.78 ppm, 1H, d, J=13.18 Hz; 2.13 ppm, 2H, s.

Example 286

(4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamideExample 287A

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamideExample 287B

(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-((1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamideProcedure 85

At −78° C. to a mixture of(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide(Example 285, 36 mg, 0.06 mmol) and K₂CO₃ (28 mg, 0.2 mmol) in acetone(0.5 mL) was added KMnO₄ (9 mg, 0.06 mmol). The resulted purple reactionmixture was stirred at −78° C. for 1 h, then at 0° C. for 30 min. Thereaction mixture was diluted with EtOAc (25 mL) and the organic layerwas washed by 1 N HCl (2×mL), dried over MgSO₄, filtered andconcentrated. The resulting residue was purified by preparative HPLCShimadzu-YMC Sunfire 5p column, 30×100 mm eluting with 60-100% MeOH (90%in H₂O, 0.1% TFA) gradient over 14 min with flow rate 40 mL/min and UVdetection at 220 nm.4,4,4-Trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 286) was eluted at a retention time of 12.86 min and wasisolated as a clear oil (15 mg, yield 39%). LCMS: RT=2.12 min [M+H]650.92 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=4.36 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.92 ppm, 1H, d,J=6.15 Hz; 7.19 ppm, 5H, m; 7.06 ppm, 1H, t, J=8.57 Hz; 6.97 ppm, 5H, m;6.71 ppm, 1H, m; 6.62 ppm, 2H, t, J=6.37 Hz; 5.88 ppm, 1H, m; 4.51 ppm,1H, s; 4.11 ppm, 1H, m; 3.56 ppm, 1H, m; 3.25 ppm, 1H, m.

The diastereomer mixture of4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 286, 189 mg, 0.3 mmol) was separated by chiral preparative HPLCchiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flowrate 50 mL/min.(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287A) was eluted at a retention time of 52 min and(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287B) was eluted at a retention time of 70 min. Thestereochemistry of(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287A) and(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287B) was assigned arbitrarily.

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287A) was further purified by ISCO chromatography (40 g column,flow rate 20 mL/min) using hexanes/EtOAc (0-30% over 30 min) to give(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287A) as a white solid at a retention time of 28 min (95 mg,50% yield). LCMS: RT=2.12 min [M+H] 650.00 (Phenomenex Luna C18 column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.241 min, Purity 100%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400MHz ¹H (CDCl₃) 7.95 ppm, 1H, s; 7.22 ppm, 2H, m; 7.16 ppm, 2H, t, J=7.25Hz; 6.99 ppm, 8H, m; 6.62 ppm, 2H, d, J=7.47 Hz; 5.89 ppm, 1H, t,J=52.95 Hz; 4.52 ppm, 1H, d, J=6.15 Hz; 4.08 ppm, 1H, d, J=3.95 Hz; 3.53ppm, 2H, d, J=13.18 Hz.

(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287B) was further purified by ISCO chromatography (40 g column,flow rate 20 mL/min) using hexanes/EtOAc (0-30% over 30 min) to give(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 287B) as a clear oil at a retention time of 28 min (57 mg, 30%yield). LCMS: RT=2.12 min [M+H] 650.00 (Phenomenex Luna C18 column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.285 min, Purity 100%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400MHz ¹H (CDCl₃) ¹H NMR (400 MHz, Solvent) δ ppm 7.95 ppm, 1H, s; 7.20ppm, 6H, m; 7.05 ppm, 2H, t, J=8.57 Hz; 6.93 ppm, 1H, d, J=8.79 Hz; 6.71ppm, 2H, m; 6.63 ppm, 2H, d, J=7.03 Hz; 5.85 ppm, 1H, tt, J=52.95, 2.64Hz; 4.49 ppm, 1H, d, J=6.15 Hz; 4.02 ppm, 1H, d, J=13.62 Hz; 3.79 ppm,1H, d, J=6.15 Hz; 3.59 ppm, 1H, d, J=13.18 Hz.

Example 288

1,1,1-trifluoro-4-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-2-phenylbutane-2,3-diolProcedure 87

A mixture of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine,prepared as described in Procedure 3, 4, 5 and 6, (20 mg, 0.047 mmol),2,2,2-trifluoro-1-(oxiran-2-yl)-1-phenylethanol (63 mg, 0.28 mmol), andYb(CF₃OSO₂)₃ (10 mg) in dichloroethane (0.5 mL) were heated at 45° C.for 72 h. The reaction mixture was concentrated and the residue waspurified by preparative HPLC Shimadzu-YMC Sunfire 5μ column, 30×100 mmeluting with 40-100% MeOH (90% in H₂O, 0.1% TFA) gradient over 10 minwith flow rate 40 mL/min and UV detection at 220 nm.1,1,1-Trifluoro-4-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-2-phenylbutane-2,3-diol(Example 288) was eluted at a retention time of 9.11 min and wasisolated as a clear oil (11 mg, yield 37%). LCMS: RT=1.85 min [M+H]643.95 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=4.20 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.34 ppm, 5H, m;7.17 ppm, 1H, t, J=7.47 Hz; 7.07 ppm, 4H, m; 6.95 ppm, 2H, m; 6.84 ppm,1H, m; 6.73 ppm, 2H, m; 6.44 ppm, 2H, d, J=7.47 Hz; 5.86 ppm, 1H, m;4.02 ppm, 2H, dd, J=6.59, 3.95 Hz; 3.33 ppm, 2H, m; 2.32 ppm, 1H, dt,J=12.74, 4.61 Hz; 2.18 ppm, 1H, ddd, J=14.72, 12.52, 7.03 Hz.

Example 289

(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(1H-indol-3-yl)-2-oxoacetamideProcedure 88

At 0° C., to a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine,prepared as described in Procedure 3, 4, 5 and 6, (20 mg, 0.045 mmol)and 2-(1H-indol-3-yl)-2-oxoacetyl chloride (10 mg, 0.05 mmol) in THF(0.5 mL) was added dropwise diisopropylethylamine (10 μL, 0.06 mmol).The reaction mixture was stirred at 0° C. for 3 h. The reaction mixturewas concentrated and the residue was purified by preparative HPLCShimadzu-YMC Sunfire 5μ column, 30×100 mm eluting with 40-100% MeOH (90%in H₂O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UVdetection at 220 nm.(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(1H-indol-3-yl)-2-oxoacetamide(Example 289) was eluted at a retention time of 11.65 min and wasisolated as a clear oil (13 mg, yield 48%). LCMS: RT=2.20 min [M+H]596.96 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=4.45 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm). NMR: 400 MHz ¹H (CDCl₃) 8.98 ppm, 1H, d,J=3.52 Hz; 8.83 ppm, 1H, s; 8.43 ppm, 1H, s; 8.40 ppm, 1H, d, J=7.03 Hz;7.42 ppm, 1H, m; 7.34 ppm, 2H, m; 7.14 ppm, 5H, m; 7.01 ppm, 2H, t,J=8.57 Hz; 6.93 ppm, 3H, m; 6.68 ppm, 2H, d, J=7.03 Hz; 5.86 ppm, 1H,tt, J=53.06, 2.86, 2.64 Hz; 3.96 ppm, 1H, d, J=12.74 Hz; 3.82 ppm, 1H,m.

Example 290

1,1,1-trifluoro-4-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-2-(trifluoromethyl)butane-2,3-diolProcedure 89

A mixture of4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,3-dihydroxy-3-(trifluoromethyl)butanamide(Example 286, 20 mg, 0.031 mmol) and BH₃/THF (248 μL, 1.0 M solution inTHF, 0.248 mmol) in THF (0.5 mL) was heated at 100° C. under microwaveirradiation for 30 min. The reaction mixture was concentrated, dilutedwith EtOAc (25 mL) and the organic layer was washed with saturatedNa₂CO₃ (25 mL), dried over MgSO₄, filtered and concentrated. Theresulting residue was purified by preparative HPLC Shimadzu-YMC Sunfire5μ column, 30×100 mm eluting with 40-100% MeOH (90% in H₂O, 0.1% TFA)gradient over 12 min with flow rate 40 mL/min and UV detection at 220nm.1,1,1-Trifluoro-4-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-2-(trifluoromethyl)butane-2,3-diol(Example 290) was eluted at a retention time of 11.09 min and isolatedas a clear oil (12 mg, yield 62%). LCMS: RT=1.95 min [M+H] 636.38(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC:RT=4.01 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.21 ppm, 4H, dd, J=8.57,5.49 Hz; 7.15 ppm, 2H, t, J=7.25 Hz; 7.06 ppm, 2H, t, J=8.57 Hz; 6.90ppm, 1H, d, J=8.35 Hz; 6.80 ppm, 1H, dd, J=9.67, 2.20 Hz; 6.77 ppm, 1H,s; 6.60 ppm, 2H, d, J=6.59 Hz; 5.87 ppm, 1H, tt, J=52.95, 2.86 Hz; 3.84ppm, 1H, t, J=5.71 Hz; 3.59 ppm, 1H, m; 3.46 ppm, 1H, m; 3.07 ppm, 1H,dd, J=12.74, 6.15 Hz; 2.86 ppm, 1H, dd, J=12.96, 5.49 Hz.

Example 291

(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamideProcedure 90

A round bottom flask was charged with IIDQ polystyrene resin (493 mg,1.5 mmol/g, 0.74 mmol) and acetonitrile (5 mL) and sealed with a rubberseptum. The suspension was vacuumed and reflushed with argon threetimes. To the resulting slurry was added a solution of(R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine,prepared as described in Procedures 109, 110, 111, 112, 113, 114, (180mg, 0.37 mmol) and 4,4,4-trifluoro-3-(trifluoromethyl)crotonic acid (93mg, 0.45 mmol) in acetonitrile (5 mL) and the reaction mixture wasstirred at room temperature for 18 h. The reaction mixture was filteredand the filtrate was concentrated under reduced pressure and purified byISCO chromatography (40 g column) using hexane/EtOAc (0-15% over 30 min)to give(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide(Example 291) as a white solid at a retention time of 20 min (199 mg,74% yield). LCMS: RT=2.18 min [M+H] 674.33 (Phenomenex Luna C18 column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.25 min, Purity 98%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400MHz ¹H (CDCl₃) 7.19 ppm, 3H, m; 7.02 ppm, 1H, dd, J=10.55, 8.79 Hz; 6.95ppm, 3H, m; 6.85 ppm, 1H, s; 6.67 ppm, 3H, d, J=7.03 Hz; 6.62 ppm, 1H,m; 6.13 ppm, 1H, s; 5.88 ppm, 1H, tt, J=53.00, 2.86, 2.75 Hz; 4.36 ppm,1H, ddd, J=11.97, 6.15, 6.04 Hz; 3.99 ppm, 1H, d, J=13.18 Hz; 3.71 ppm,1H, d, J=13.18 Hz; 1.26 ppm, 6H, m.

Example 292A

(S)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamideExample 292B

(R)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamideProcedure 91

At 0° C. to a solution of(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide(Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg,0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL,chlorine wt % 10-3%, 0.58 mmol). The reaction mixture was stirred at 0°C. for 10 min, then at rt for 1 h. The solvents were removed underreduced pressure and the residue was diluted with EtOAc (30 mL), washedwith saturated Na₂SO₃ (30 mL), dried over MgSO₄, filtered andconcentrated. The resulting residue was right away purified by ISCOchromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc(0-10% over 30 min) to giveN-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamideas a diastereomer mixture at a retention time of 26 min (97 mg, 74%yield). The diastereomer mixture was separated by Chiral preparativeHPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane withflow rate 50 mL/min.

(S)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292A) was eluted at a retention time of 30 min and isolated asa clear oil (50 mg, yield 51%). LCMS: RT=2.25 min [M+H] 690.30(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC:RT=4.225 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.20 ppm, 3H, ddd,J=14.72, 7.25, 7.03 Hz; 6.98 ppm, 3H, m; 6.90 ppm, 1H, s; 6.60 ppm, 5H,m; 5.87 ppm, 1H, t; 4.31 ppm, 1H, ddd, J=12.19, 6.04, 5.93 Hz; 4.10 ppm,1H, d, J=13.18 Hz; 3.95 ppm, 1H, s; 3.51 ppm, 1H, d, J=13.18 Hz; 1.28ppm, 3H, d, J=5.71 Hz; 1.21 ppm, 3H, d, J=5.71 Hz.

(R)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292B) was eluted at a retention time of 40 min and isolated asa clear oil (38 mg, yield 39%). LCMS: RT=2.27 min [M+H] 690.30(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC:RT=4.20 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.20 ppm, 3H, m; 7.05ppm, 1H, m; 6.95 ppm, 1H, d, J=7.91 Hz; 6.85 ppm, 2H, m; 6.72 ppm, 2H,m; 6.64 ppm, 2H, d, J=7.47 Hz; 6.59 ppm, 1H, s; 5.87 ppm, 1H, m; 4.36ppm, 1H, m; 3.92 ppm, 1H, m; 3.88 ppm, 1H, m; 3.70 ppm, 1H, m; 1.26 ppm,6H, 9 m.

The relative stereochemistry of(S)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292A) and(R)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292B) was assigned arbitrarily.

Example 293

(S)-2-amino-4,4,4-trifluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamideProcedure 92

A solution of NH₃ in MeOH (7 M, 1.0 mL) was added to(S)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292A, 28 mg, 0.04 mmol) and the reaction mixture was stirred atrt for 3 h. The reaction mixture was concentrated and purified bypreparative HPLC (Shimadzu-Phenomenex Luna AXIA 5μ column, 21.2×100 mmeluting with 30-100% ACN (90% in H₂O, 0.1% TFA) gradient over 14 minwith flow rate 20 mL/min and UV detection at 220 nm).(S)-2-amino-4,4,4-trifluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide(Example 293) was eluted at a retention time of 12.83 min and isolatedas a clear oil (20 mg, yield 70%). LCMS: RT=2.11 min [M+H] 707.41(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC:RT=3.99 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 9.00 ppm, 1H, s; 7.19 ppm,3H, m; 7.04 ppm, 1H, m; 6.93 ppm, 1H, d, J=8.79 Hz; 6.76 ppm, 4H, m;6.64 ppm, 2H, d, J=7.03 Hz; 5.8 ppm, 1H, m; 4.38 ppm, 1H, dq, J=6.15,6.01 Hz; 3.87 ppm, 1H, m; 3.70 ppm, 2H, m; 1.89 ppm, 2H, s; 1.28 ppm,6H, m.

Example 294

(S)-2,4,4,4-tetrafluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamideProcedure 93

To a solution of(S)-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(Example 292A, 25 mg, 0.036 mmol) in THF (0.5 mL) was added TBAF (72 μL,1.0 M solution in THF, 0.072 mmol). The reaction mixture was heated at60° C. under microwave irradiation for 10 min. The solvent was removedunder reduced pressure and the residue was purified by preparative HPLC(Shimadzu-YMC ODS 5μ column, 20×100 mm eluting with 30-100% ACN (90% inH₂O, 0.1% TFA) gradient over 18 min with flow rate 20 mL/min and UVdetection at 220 nm).(S)-2,4,4,4-tetrafluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide(Example 294) was eluted at a retention time of 17.28 min and wasisolated as a clear oil (14 mg, yield 55%). The stereochemistry of(S)-2,4,4,4-tetrafluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide(Example 294) was assigned arbitrarily. LCMS: RT=2.22 min [M+H] 710.39(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC:RT=4.18 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.26 ppm, 1H, m; 7.21ppm, 3H, m; 7.07 ppm, 1H, m; 6.96 ppm, 1H, d, J=8.79 Hz; 6.78 ppm, 4H,m; 6.64 ppm, 2H, d, J=7.15 Hz; 6.50 ppm, 1H, s; 5.87 ppm, 1H, tt,J=52.97, 2.61, 2.47 Hz; 5.10 ppm, 1H, d, J=46.17 Hz; 4.41 ppm, 1H, dt,J=12.09, 6.05 Hz; 3.97 ppm, 1H, d, J=13.19 Hz; 3.58 ppm, 1H, d, J=13.19Hz; 1.30 ppm, 6H, t, J=6.32 Hz.

Example 295A

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamideExample 295B

(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamideProcedure 94

To a mixture of diastereomers ofN-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(40 mg, 0.069 mmol), prepared as described in Procedure 90 and 91, wasadded Yb(CF₃SO₃)₃ (10 mg) and methylamine in MeOH (0.2 mL, 2 M solutionin MeOH). The reaction was heated at 60° C. under microwave irradiationfor 10 min and then concentrated under reduced pressure. The residue wasdiluted with EtOAc (25 mL) and washed with saturated Na₂CO₃, dried overMgSO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by preparative HPLC Shimadzu-YMC-ODS-A 5μ column,20×100 mm eluting with 30-100% MeOH (90% in H₂O, 0.1% TFA) gradient over30 min with flow rate 20 mL/min and UV detection at 220 nm.

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamide(Example 295A) was eluted at a retention time of 22.96 min and isolatedas a clear oil (4 mg, yield 9%). LCMS: RT=4.17 min [M+H] 615.3(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 10 mM NH₄OAc; 4 mL/min, monitoring at 220 nm);HPLC: RT=3.87 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) 9.24 ppm, 1H, s;7.54 ppm, 1H, s; 7.30 ppm, 3H, m; 7.20 ppm, 3H, m; 7.01 ppm, 2H, t,J=8.35 Hz; 6.85 ppm, 2H, m; 6.60 ppm, 2H, d, J=7.03 Hz; 4.29 ppm, 1H, d,J=12.74 Hz; 3.47 ppm, 1H, d, J=12.74 Hz; 3.32 ppm, 1H, s; 2.32 ppm, 3H,s.

(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamide(Example 295B) was eluted at a retention time of 23.45 min and isolatedas a clear oil (5 mg, yield 11%). LCMS: 4.16 min [M+H] 615.3 (PhenomenexLuna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 10 mM NH₄OAc; 4 mL/min, monitoring at 220 nm); HPLC: RT=3.93min, Purity 92% (Phenomenex Luna C18 column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoringat 220 nm) NMR: 400 MHz ¹H (CDCl₃) 9.06 ppm, 1H, s; 7.30 ppm, 2H, m;7.23 ppm, 3H, d, J=5.71 Hz; 7.17 ppm, 2H, t, J=7.25 Hz; 7.08 ppm, 2H, t,J=8.57 Hz; 7.00 ppm, 1H, m; 6.91 ppm, 1H, d, J=10.11 Hz; 6.60 ppm, 2H,d, J=7.03 Hz; 4.14 ppm, 1H, m; 3.98 ppm, 1H, s; 3.52 ppm, 2H, m; 3.39ppm, 2H, m; 2.37 ppm, 3H, s.

The stereochemistry of(S)-4,4,4-Trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamide(Example 295A) and(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(methylamino)-3-(trifluoromethyl)butanamideisomer B (Example 295B)was assigned arbitrarily.

Example 296

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(isopropylamino)-3-(trifluoromethyl)butanamideProcedure 95

To a solution of(S)-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide(20 mg, 0.034 mmol), prepared as described in Procedure 90 and 91, inACN (0.5 mL) was added Yb(CF₃SO₃)₃ (10 mg) and isopropylamine (10 μL,0.1 mmol). The reaction mixture was heated at 60° C. under microwaveirradiation for 10 min and then concentrated under reduced pressure. Theresidue was diluted with EtOAc (25 mL) and the organic layer was washedby saturated Na₂CO₃, dried over MgSO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by preparative HPLCShimadzu-YMC-ODS-A 5μ column, 20×100 mm eluting with 30-100% MeOH (90%in H₂O, 0.1% TFA) gradient over 30 min with flow rate 20 mL/min and UVdetection at 220 nm.(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxy-2-(isopropylamino)-3-(trifluoromethyl)butanamide(Example 296) was eluted at a retention time of 27.36 min and isolatedas a clear oil (12 mg, yield 54%). LCMS: RT=2.15 min [M+H] 643.4(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm); HPLC:RT=4.293 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm). NMR: 400 MHz ¹H (CDCl₃) 9.23 ppm, 1H, s; 7.77ppm, 1H, s; 7.30 ppm, 3H, m; 7.20 ppm, 1H, m; 7.14 ppm, 2H, t, J=7.25Hz; 7.02 ppm, 2H, t, J=8.35 Hz; 6.93 ppm, 1H, d, J=4.83 Hz; 6.60 ppm,2H, d, J=7.03 Hz; 4.29 ppm, 1H, d, J=13.18 Hz; 3.51 ppm, 1H, d, J=5.27Hz; 3.47 ppm, 1H, d, J=12.74 Hz; 2.74 ppm, 1H, m; 1.87 ppm, 1H, s; 1.04ppm, 3H, d, J=6.15 Hz; 0.71 ppm, 3H, d, J=6.15 Hz. The stereochemistryof(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-hydroxy-2-(isopropylamino)-3-(trifluoromethyl)butanamide(Example 296) was assigned arbitrarily.

Example 297

(R)-N-(2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 96

A solution of2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)acetonitrileprepared as described in Procedure 3, 4 and 73 (72% yield, 453 mg, 1.1mmol) in MeOH (18 mL) was cooled to 0° C. and saturated with HCl gas.The resulting solution was heated at reflux overnight. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between EtOAc and sat. NaCl. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by ISCO (40 g silica gelcolumn, 0-40% EtOAc/hexane over 50 min) to yield methyl2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)acetateas a colorless oil (394 mg, 80% yield). LCMS: RT=2.05 min [M+H] 446.97(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm); HPLC: RT=4.22 min (Phenomenex Luna C18 4.6×50 mm column, elutingwith 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4 mL/min, wavelength220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.53 (1H, d, J=6.59 Hz),7.47-7.51 (1H, m), 7.19 (1H, t, J=9.23 Hz), 6.9-6.97 (3H, m), 5.76-6.03(1H, m), 3.78 (3H, s).

Procedure 97

To a suspension of NaH (60% in oil, 66 mg, 1.65 mmol) in DMF (3 mL) at0° C. was added a solution of methyl2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)acetate(600 mg, 1.34 mmol) in one portion. The reaction mixture was stirred at0° C. for 10 min followed by addition of a solution of4-bromobenzylbromide (343 mg, 1.37 mmol) in DMF (2 mL). The reaction wasstirred at 0° C. for 5 min and quenched by the addition of saturatedNH₄Cl. The mixture was extracted with EtOAc (2×30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated to give methyl3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoateas a colorless oil (865 mg, 100% yield). LCMS: RT=2.26 min, noionization (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.48 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.29-7.33 (1H,m), 7.21-7.27 (4H, m), 7.11 (1H, t, J=9.23 Hz), 6.94 (1H, d, J=8.79 Hz),6.82 (1H, d, J=9.67 Hz), 6.80 (1H, s), 6.52 (2H, d, J=8.35 Hz), 5.87(1H, t, J=53.2 Hz), 3.75 (3H, s), 3.56-3.66 (2H, m).

A mixture of methyl3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoate(865 mg, 1.34 mmol) in MeOH (10 mL)/THF (20 mL) and LiOH (2 N, 10 mL)was stirred at rt overnight. The reaction mixture was made acidic byaddition of 1 N HCl to pH=1˜2 and concentrated. The resulting residuewas partitioned between EtOAc and sat. NaCl. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by ISCO (40 g siligel column,0-10% MeOH/DCM over 30 min) to yield3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoicacid as a colorless oil (650 mg, 81% yield). LCMS: RT=2.17 min [M+H]600.88 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.45 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm).

Procedure 98

At 0° C. to a solution of3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoicacid (1.59 g, 2.64 mmol) in acetone (30 mL) was added TEA (442 μL, 3.17mmol) followed by ethyl chloroformate (303 μL, 3.17 mmol). The reactionmixture was stirred at 0° C. for 45 min and NaN₃ (343 mg, 5.28 mmol) wasadded. The reaction was stirred at 0° C. for 1 h, quenched by theaddition of water and the aqueous layer was extracted with toluene (3×30mL). The combined organic layers were washed with sat. NaCl, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was diluted with toluene (10 mL) and heated at 90° C.for 6 h. The reaction mixture was concentrated under reduced pressureand the residue was dissolved in t-BuOH/THF (1:1, 20 mL) and treatedwith t-BuOK/t-BuOH (1 N, 13.2 mL, 13.2 mmol). The reaction mixture wasstirred at rt overnight, then heated at 85° C. for 3 h. The reactionmixture was quenched by the addition of water and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed with sat.NaCl, dried over magnesium sulfate, filtered and concentrated. Theresidue was purified by ISCO (40 g siligel column, 0-40% EtOAc/hexaneover 40 min to yield2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamineas a colorless oil (1.2 g, 82% yield). LCMS: RT=1.82 min [M+H] 556.8(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.61 (1H, d, J=6.15 Hz), 7.48-7.53(1H, m), 7.30 (1H, d, J=7.91 Hz), 7.15 (1H, t, J=9.23 Hz), 6.96-7.00(2H, m), 6.89 (1H, d, J=8.79 Hz), 6.61 (2H, d, J=7.91 Hz), 5.89 (1H, t,J=53 Hz), 3.49 (1H, d, J=13.6 Hz), 3.43 (1H, d, J=13.6 Hz), 1.50-1.65(2H, m).

2-(4-Bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine(racemic, 510 mg) was subjected to chiral preparative HPLC separation(chiral OD 10 micron 4.6×250 mm column, eluting with 20%iPA/heptane/0.1% DEA) to give(R)-2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine(211 mg) as a colorless oil and(S)-2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine(195 mg) as colorless oil. For(R)-2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine:chiral analytical HPLC: RT=6.0 min, 100% ee (chiral OD 10 micron 4.6×250mm column, eluting with 20% IPA/heptane/0.1% DEA, flow rate 1 mL/min,wavelength 220 nm); LCMS: RT=1.82 min [M+H] 556.8 (Phenomenex Luna C184.6×30 mm column, eluting with 10-90% MeOH/H₂O containing 0.1% TFA, 2min gradient, flow rate 5 mL/min, wavelength 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.61 (1H, d, J=6.15 Hz), 7.48-7.53 (1H, m), 7.30 (1H, d,J=7.91 Hz), 7.15 (1H, t, J=9.23 Hz), 6.96-7.00 (2H, m), 6.89 (1H, d,J=8.79 Hz), 6.61 (2H, d, J=7.91 Hz), 5.89 (1H, t, J=53 Hz), 3.49 (1H, d,J=13.6 Hz), 3.43 (1H, d, J=13.6 Hz), 1.50-1.65 (2H, m). For(S)-2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamineisomer B: chiral analytical HPLC: RT=7.5 min, 100% ee (chiral OD 10micron 4.6×250 mm column, eluting with 20% IPA/heptane/0.1% DEA, flowrate 1 mL/min, wavelength 220 nm); LCMS: RT=1.82 min [M+H] 556.8(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm). ¹H NMR (400 MHz, CDCL₃) δ ppm 7.61 (1H, d, J=6.15 Hz), 7.48-7.53(1H, m), 7.30 (1H, d, J=7.91 Hz), 7.15 (1H, t, J=9.23 Hz), 6.96-7.00(2H, m), 6.89 (1H, d, J=8.79 Hz), 6.61 (2H, d, J=7.91 Hz), 5.89 (1H, t,J=53 Hz), 3.49 (1H, d, J=13.6 Hz), 3.43 (1H, d, J=13.6 Hz), 1.50-1.65(2H, m).

Following Procedure 7,(R)-N-(2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 297) was prepared as a white foam (471 mg, 88% yield). LCMS:RT=2.25 min [M+H] 761.8 (Phenomenex Luna C18 4.6×30 mm column, elutingwith 10-90% MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5mL/min, wavelength 220 nm); HPLC: RT=4.52 min (Phenomenex Luna C184.6×50 mm column, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flowrate 4 mL/min, wavelength 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96(1H, dd, J=6.59, 2.20 Hz), 7.81-7.85 (1H, m), 7.39-7.44 (2H, m),7.30-7.34 (2H, m), 7.21 (1H, t, J=9.45 Hz), 6.99 (1H, d, J=8.79 Hz),6.79-6.84 (2H, m), 6.57 (1H, s), 6.55 (2H, d, J=8.35 Hz), 5.89 (1H, t,J=54 Hz), 3.95 (1H, d, J=13.2 Hz), 3.86 (1H, d, J=13.2 Hz).

Example 298

(R)-N-(2-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethyl)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 99

A mixture of(R)-N-(2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 297, 20 mg, 0.028 mmol) and azidotributyltin (38 μL, 0.14 mmol)in toluene was heated at 100° C. overnight. The reaction mixture wasconcentrated under reduced pressure and the residue was purified by ISCO(4 g silica gel column, 0-10% MeOH/DCM) to give(R)-N-(2-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethyl)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 298) as a white solid (11 mg, 52% yield). LCMS: RT=2.07 min[M+H] 752.3 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.26 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.98 (1H, s),7.95-7.98 (2H, m), 7.71 (2H, d, J=8.35 Hz), 7.49 (1H, dd, J=7.47, 3.95Hz), 7.34-7.42 (2H, m), 7.22 (1H, t, J=9.45 Hz), 7.04 (1H, d, J=10.11Hz), 6.94-6.98 (2H, m), 6.84 (2H, d, J=8.35 Hz), 6.18 (1H, t, J=52.3Hz), 4.11 (1H, d, J=12.7), 4.11 (1H, d, J=12.7).

Example 299

(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 100

To a solution of (R)-methyl4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoateprepared as described in Procedure 96, 97, 98, 56 and 57 (29 mg, 0.039mmol) in THF at −78° C. was added a solution of lithiumtriethylborohydride (1.0 M in THF, 0.5 mL, 0.5 mmol). The resultingmixture was stirred at −78° C. for 1.5 h. The reaction was quenched byaddition of 1 N NaOH (1 mL) and the aqueous layer was extracted withEtOAc (15 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over min)to yield(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 299) as a colorless film (22 mg, 79% yield). LCMS: RT=2.10 min[M+H] 714.31 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98-7.80 (1H,m), 7.85-7.89 (1H, m), 7.39-7.43 (3H, m), 7.31 (1H, t, J=9.23 Hz),7.19-7.27 (1H, m), 6.99 (1H, d, J=8.79 Hz), 6.76-6.83 (5H, m), 5.89 (1H,t, J=53.0 Hz), 4.16 (1H, d, J=13.18 Hz), 4.02 (1H, d, J=13.18 Hz).

Example 300

(R)-N-(2-(4-(aminomethyl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 101

To a solution of(R)-N-(2-(4-cyanophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide,prepared as described in Procedure 56, (77% yield, 20 mg, 0.02 mmol) inTHF (1.5 mL) at rt was added LAH (1.0 M in THF). The reaction mixturewas stirred at rt for 5 h, then quenched by addition of 2 N LiOH. Thesolid was removed by filtration and the filtrate was concentrated. Theresulting residue was purified by prep HPLC (YMC Sunfire 5μ C18 30×100mm column, eluting with 20-90% MeOH/H₂O containing 0.1% TFA, 10 mingradient, flow rate 40 mL/min, wavelength 220 nm) to provide(R)-N-(2-(4-(aminomethyl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 300) as a colorless film (5 mg, 36% yield). LCMS: RT=1.8 min[M+H] 713.26 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.31 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.95 (1H, d,J=6.59 Hz), 7.46-7.48 (1H, m), 7.36 7.41 (2H, m), 7.22 (1H, t, J=9.45Hz), 7.16 (2H, d, J=7.91 Hz), 6.99 (2H, dd, J=16.48, 9.45 Hz), 6.93 (1H,s), 6.73 (2H, d, J=7.91 Hz), 6.21H, t, J=49.7 Hz), 4.01-4.06 (1H, m),3.93-3.99 (3H, m).

Example 301

(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-((methylamino)methyl)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 102

A solution of(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 299, 20 mg, 0.028 mmol) in SOCl₂ was stirred at rt overnight.The reaction mixture was concentrated and the residue was treated with asolution of methyl amine in methanol (1.0 M, 2.0 mL, 2.0 mmol) at rtovernight. The solvent was removed and the residue was purified by prepHPLC (YMC Sunfire 5μ C18 30×100 mm column, eluting with 20-90% MeOH/H₂Ocontaining 0.1% TFA, 10 min gradient, flow rate 40 mL/min, wavelength220 nm) to provide(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-((methylamino)methyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 301) as a white solid (13 mg, 65% yield). LCMS: RT=2.02 min[M+H]=727.48 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=3.11 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.57-8.06 (2H,m), 7.48-7.57 (1H, m), 7.43-7.49 (2H, m), 7.30 (1H, t, J=9.45 Hz), 7.25(2H, d, J=7.91 Hz), 7.00-7.10 (3H, m), 6.82 (2H, d, J=8.35 Hz), 6.29(1H, t, J=46.6 Hz), 4.03-4.15 (4H, m), 2.65 (3H, s).

Example 302

(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(methylcarbamoyl)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 103

A solution of(R)-4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoicacid, prepared as described in Procedure 97, 98, 99 and 100, (65 mg,0.09 mmol) in SOCl₂ was heated at 60° C. overnight. The reaction mixturewas concentrated and 25 mg of the resulting residue was treated with asolution of methyl amine in methanol (1.0 M, 2.0 mL, 2.0 mmol) at rtovernight. The solvent was removed and the residue was purified by ISCO(12 g column, 0-20% EtOAc/hexane) to yield(R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(methylcarbamoyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 302) as a white solid (14 mg, 85% yield). LCMS: RT=2.16 min[M+H] 741.55 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (1H, d,J=5.71 Hz), 7.81-7.86 (1H, m), 7.50 (2H, d, J=7.91 Hz), 7.43 (2H, d,J=5.27 Hz), 7.25-7.31 (1H, m), 7.19 (1H, t, J=9.45 Hz), 6.97 (1H, d,J=8.35 Hz), 6.82 (2H, d, J=4.83 Hz), 6.74 (2H, d, J=7.91 Hz), 6.05 (1H,d, J=4.83 Hz), 5.88 (1H, t, J=52.1), 4.04 (1H, d, J=13.2), 3.95 (1H, d,J=13.2), 2.94 (3H, d, J=4.83 Hz).

Example 303

(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethyl)-3-(trifluoromethyl)benzamideProcedure 104

To a solution of 5-methyl-2-trityl-2H-tetrazole (0.90 g, 2.76 mmol) indry THF (20 mL) at −78° C. under argon was added dropwise n-BuLi (2.5 Min hexane, 1.2 mL, 3 mmol). The resulting solution was stirred at −78°C. for 1 h, followed by the dropwise addition of a solution of(R)-N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide,prepared as described in Procedure 3, 4 and 5, (0.40 g, 0.91 mmol) inTHF (5 mL). The reaction mixture was stirred at −78° C. to −70° C.overnight. The reaction mixture was quenched by addition of sat. NH₄Cland the aqueous layer was extracted with Et₂O (2×) and the combinedorganic layers were washed with H₂O, sat. NaCl, dried over Na₂SO₄,filtered and concentrated. The residue was purified by ISCO flashchromatography (silica gel, hexanes/EtOAc) to give(R)-N-((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamideas the fast eluting diastereomer (90 mg, 13% yield) and(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamideas the slow eluting diastereomer (85 mg, 12% yield).

To a solution of(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide(60 mg, 0.079 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (1 mL).The reaction mixture was stirred at room temperature for 20 min, thenconcentrated to yield(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine.LCMS: RT=2.66 min [M+H] 418.55 (Phenomenex Luna C18 4.6×50 mm column,eluting with 10-90% MeOH/H₂O containing 0.1% TFA, 4 min gradient, flowrate 4 mL/min, wavelength 220 nm). To a solution of((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanaminein THF (3 mL) and MeOH (0.5 mL) was added (diazomethyl)trimethylsilane(2.0 M in hexanes, 0.05 mL). After stirring at room temperate for 20min, the reaction mixture was concentrated and purified by ISCO flashcolumn chromatography (silica gel, EtOAc) to give((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine(10 mg, yield: 30%). LCMS: RT=2.83 min [M+H] 432.57 (Phenomenex Luna C18column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; 4 mL/min, monitoring at 220 nm).

Following Procedure 7,((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine(Example 303) was obtained (10 mg, yield 67%). LCMS: RT=3.86 min [M+H]622.01 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCL₃) ppm 8.30 (m, 2H), 8.19 (m, 1H), 7.37 (m,3H), 7.05 (m, 4H), 6.92 (d, J=8.6 Hz, 1H), 5.89 (tt, J=53.05, 3.03 Hz,1H), 4.26 (s, 3H),

Example 304

(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)ureaProcedure 105

To a solution of(R)-1-cyclopentyl-3-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea,prepared as described in Procedure 59, (20 mg, 0.039 mmol) in DMF (0.1mL) was added K₂CO₃ (12 mg, 0.086 mmol), followed by 2,2-dimethyloxirane(28 mg, 0.39 mmol). The resulting mixture was stirred at 60° C. for 16h. The reaction mixture was filtered and the solid was washed withEtOAc. The filtrate was washed with H₂O, sat. NaCl and dried over Na₂SO₄and filtered. The organic solvent was evaporated under reduced pressureand the residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30mm, 5μ column eluting with 10-90% ACN/H₂O over 10 minutes containing0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford(R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea(Example 304) as white lyophillate (11 mg, 56% yield). LCMS: RT=4.066min [M+H] 577.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm (retention time, column type, size, solvent, flowrate, gradient). NMR: 400 MHz ¹H (CD₃OD) ppm 1.27 (d, J=2.20 Hz, 6H),1.32-1.49 (m, 2H), 1.54-1.76 (m, 4H), 1.81-1.98 (m, 2H), 3.53 (d, J=9.23Hz, 1H), 3.69 (d, J=9.23 Hz, 1H), 3.78 (d, J=12.74 Hz, 1H), 3.91 (t,J=6.15 Hz, 1H), 4.02 (d, J=12.74 Hz, 1H), 6.63-6.70 (m, 1H), 6.72-6.79(m, 3H), 7.01 (dd, J=10.99, 8.79 Hz, 1H), 7.09-7.20 (m, 3H), 7.27-7.42(m, 3H).

Example 305

(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 106

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenyethyl)-3-(trifluoromethyl)benzamide(Example 264, 100 mg, 0.158 mmol) in toluene (0.2 ml) was added Na₂CO₃(25 mg, 0.235 mmol) and catalystical amount of [Ir(cod)Cl]₂ (2 mg),followed by vinyl acetate (68 mg, 0.79 mmol). The reaction mixture wasstirred at 100° C. for 16 h. The resulting mixture was filtered and thesolid was washed with CH₂Cl₂. The CH₂Cl₂ layer was washed with 1 N NaOH,H₂O and dried over Na₂SO₄ and filtered. The solvent was evaporated underreduced pressure and the residue was purified by silica gel column using0 to 60% EtOAc in hexane to afford(R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideeluting out at 20% EtOAc in hexane as colorless oil (80 mg, 77%). LCMS:RT=2.237 min [M+H] 658.3 (2 min Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm. NMR: 400 MHz ¹H (CD₃OD) ppm 3.87 (d,J=12.74 Hz, 1H), 4.05-4.15 (m, 1H), 4.35 (dd, J=5.93, 1.98 Hz, 1H), 4.55(dd, J=13.84, 1.98 Hz, 1H), 6.12-6.41 (m, 1H), 6.48 (dd, J=13.62, 6.15Hz, 1H), 6.72 (d, J=7.03 Hz, 2H), 6.87-7.24 (m, 9H), 7.37-7.51 (m, 1H),7.88-8.04 (m, 2H).

Procedure 107

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(66 mg, 0.10 mmol) in 0.5 ml toluene was added Et₂Zn (1 N, 0.2 ml, 0.2mmol), followed by CH₂I₂ (16 ml, 0.2 mmol). The reaction mixture wasstirred at 120° C. for 3 h. The reaction mixture was quenched byaddition of 1 N HCl and the aqueous layer was extracted with CH₂Cl₂. Theorganic layer was washed with sat. NaHCO₃ and concentrated under reducedpressure. The resulting residue was purified by ISCO silica gel columnusing 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC(phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H₂Oover 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) toafford(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. NMR: 400 MHz ¹H (CDCl₃) ppm 0.45-0.73 (m, 4H),3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H),6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m,5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).

Example 306

(R)-N-(1-(3-tert-butoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 108

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 264, 50 mg, 0.079 mmol) in DMF (0.2 mL) was added1,1-di-tert-butoxy-N,N-dimethylmethanamine (100 μL, 0.49 mmol). Thereaction mixture was stirred at 110° C. for 5 h. The reaction mixturewas concentrated and purified by prep HPLC (phenomenex AXIA Luna 75×30mm, 5μ column eluting with 10-90% ACN/H₂O over 10 minutes containing0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford(R)-N-(1-(3-tert-butoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 306) as white lyophillate (46 mg, 81% yield). LCMS: RT=4.341min [M+H] 688.2 (4 min Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. NMR: 400 MHz ¹H (CDCl₃) ppm 1.22 (s, 9H), 3.89 (s,1H), 4.06 (d, J=13.19 Hz, 1H), 6.08-6.42 (m, 1H), 6.73 (d, J=7.15 Hz,2H), 6.91-7.21 (m, 9H), 7.39-7.44 (m, 1H), 7.94-8.00 (m, 2H).

Example 307

(R)-2,2,3,3,3-pentafluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)Procedure 109

To a solution of 4-fluoro-3-hydroxybenzoic acid (1.49 g, 9.55 mmol) inDCM (40 mL) was added TEA (1.2 mL, 8.61 mmol) followed byN,O-dimethylhydroxylamine hydrochloride (1.12 g, 11.5 mmol). Thereaction mixture was stirred at room temperature for 3 h, then dilutedwith DCM, washed with water twice, dried over Na₂SO₄, filtered andconcentrated to yield 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide asa colorless oil (1.90 g, 100% yield). LCMS: RT=0.89 min [M+H] 200.10(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

To a solution of 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (1.90 g,9.55 mmol) in DMF (8 mL) was added imidazole (740 mg, 10.8 mmol) andTBDMSCl (1.62 g, 10.8 mmol) at room temperature. The reaction mixturewas stirred for 48 h and quenched with saturated NaHCO₃. The solutionwas extracted with ether (3×) and the combined ether portions washedwith LiCl (10%), dried over Na₂SO₄, filtered and concentrated. Theresulted colorless oil was purified by ISCO chromatography (120 gcolumn) using hexanes/EtOAc (0-100% over 30 min) to give3-(tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide(RT=10-12 minutes) as a colorless oil (2.00 g, 67% yield). LCMS: RT=2.06min [M+H] 314.22 (Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.26 ppm, 2H, m; 7.02 ppm, 1H, m;3.50 ppm, 3H, s; 3.31 ppm, 3H, s; 0.97 ppm, 9H, s, 0.16 ppm, 6H, s.

Procedure 110

To a N₂ flushed, 2 L four necked flask equipped with a mechanicalstirrer, a condenser, temperature controller and a N₂ inlet, was addedpotassium trimethylsilanolate (225.0 g, 1.75 mol, tech. purify 90%),1-bromo-3,5-difluorobenzene (96.5 g, 0.5 mol) and diglyme (300 mL). Thereaction mixture was heated to 120° C. under N₂ for 5 h. After coolingto rt, the heating mantle was replaced with an ice bath. The reactionmixture was acidified with 3 N HCl solution (600 mL) below 30° C. TBME(1 L) was added and the resulting mixture was stirred below 20° C. for30 min then transferred to a 5 L separatory funnel. The organic layerwas separated and washed with water (3×500 mL), sat. NaCl (500 mL),dried over MgSO₄, filtered and concentrated in vacuo to give the crudereddish product (145.0 g). The crude material was then distillated at52-55° C./0.1 mm Hg to yield 3-bromo-5-fluorophenol as a slightly yellowoil (88.0 g, 92% yield). ¹H NMR (300 MHz, CDCl₃) δ 5.34 (s, H),6.47-6.52 (m, 1H), 6.77-6.83 (m, 2H).

To a flame dried, 1 L, three necked round bottom flask (1 L) equippedwith a temperature controller, a mechanical stirrer, a condenser and aN₂ inlet was charged 3-bromo-5-fluorophenol (57.3 g, 300 mmol),1,2-dibromotetrafluoroethane (156.0 g, 600 mmol), dry DMSO (300 mL) andCs₂CO₃ (146.6 g, 450 mmol) under N₂. The reaction mixture was heated to50° C. for 5 h. After cooling to rt, water (300 mL) and hexane (300 mL)were added. The resulting mixture was stirred at rt for 30 min. Theorganic phase was separated and the aqueous layer was extracted withhexane (300 mL). The combined organic extracts were washed with water(500 mL), sat. NaCl (500 mL), dried over MgSO₄, filtered andconcentrated in vacuo to give1-bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene (104.2 g,94% yield) containing 5% of1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.2 g).1-Bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene: ¹H NMR(300 MHz, CDCl₃) δ 6.91-6.94 (m, 1H), 7.18-7.23 (m, 2H).

To a 1 L four necked round bottom flask equipped with a temperaturecontroller, a mechanical stirrer, and a N₂ inlet, was added1-bromo-3-(2-bromo-1,1,2,2,-tetrafluoro-ethoxy)-5-fluorobenzene (104.0g, 281 mmol) and 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene(5.2 g, 18 mmol), acetic acid (300 mL). The reaction mixture was thenheated to 50° C. Zinc dust (91.9 g, 1.405 mol) was added portion wise.The reaction mixture was stirred at 50° C. for 1 h and allowed to coolto rt. Water (300 mL) and hexane (300 mL) were added. The resultingmixture was stirred at rt for 30 min. The organic phase was separatedand the aqueous layer was extracted with hexane (2×300 mL). The combinedorganic extracts were washed with water (500 mL), sat. NaCl (500 mL),dried over MgSO4, filtered and concentrated in vacuo to yield1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a slightlyyellow liquid (71 g, 87% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 5.87 (tt,J=52.7 and 2.9 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.16-7.18 (m, 2H).

Procedure 111

At −78° C. under argon, to a solution of1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M incyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide(2.00 g, 6.38 mmol) was added in one portion and the reaction mixturewas stirred at −78° C. for 1.5 h. The pale yellow solution was pouredinto 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used torinse the reaction flask. The aqueous phase was separated and extractedwith ether (20 mL). The combined ether portions were dried over Na₂SO₄,filtered and concentrated. The resulting oil was purified by ISCOchromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min)to give(3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneat a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min[M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; mL/min, monitoring at 220nm); NMR: 400 MHz ¹H (CDC₃) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm,2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.

A round bottom flask was charged with(3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone(2.09 g, 4.50 mmol), (R)-2-methylpropane-2-sulfinamide (653 mg, 5.4mmol), Ti(OEt)₄ (1.54 g, 6.76 mmol) and anhydrous THF (40 mL). Theresulting solution was heated at 75° C. under argon for 14 h. Thesolvents were removed and the residue was diluted with ether (50 mL) andsat. NaCl (20 mL). The resulting mixture was filtered through a glassfrit and the filtrate transferred to a separatory funnel. The organicportion was separated and the aqueous extracted with ether (2×20 mL).The combined organic portions were dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in hexane:EtOAc and purified byISCO chromatography (2×120 g column) using hexanes/EtOAc (0-100% over 30min) to yield(R)-N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamideat a retention time of 14 min (2.05 g, 80% yield) LCMS: RT=2.37 min[M+H] 568.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). NMR: 400 MHz ¹H (CDCl₃) 7.36 ppm, 1H, m; 7.11 ppm, 5H, m; 5.90 ppm,1H, t, J=52.73 Hz; 0.97 ppm, 9H, s; 0.18 ppm, 6H, s.

Procedure 112

At −78° C. to a solution of(R)-N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(1.0 g, 1.76 mmol) in DCM (50 mL) was added BF₃.Et₂O (0.77 mL, 3.52mmol) via syringe. After 5 min, BnMgCl solution (3.5 mL, 1.0 M solutionin ether, 3.5 mmol) was added dropwise and the reaction mixture wasstirred at −78° C. for 1 h. An additional portion of BnMgCl (3.5 mL, 1.0M solution in ether, 3.5 mmol) was added dropwise and the reaction wasstirred for an additional 1 h at −78° C. The reaction mixture was pouredinto saturated NaCl (50 mL) and the organic layer was separated. Theaqueous layer was extracted with DCM (2×20 mL) and the combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The resultingoil was purified by ISCO chromatography (120 g column) usinghexanes/EtOAc (0-100% over 30 min) to give an approximate 4:1 mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideand(S)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideat a retention time of 12 min (824 mg, 71% yield) LCMS: RT=2.43 min[M+H] 660.39 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). The diastereomeric ratio of the product was determined to be 4:1 byChiral HPLC analysis (Chiralcel® AD, 90:10 heptane:i-PrOH, 1 mL/min, 254nm, RT (minor)=4.43 min, PA=17%; RT (major)=19.28 min, PA=71%) and thediastereomeric mixture was taken on directly to the next step, Procedure112, or the diastereomers were separated as described in Procedure 114.NMR: 400 MHz ¹H (CDCl₃) 7.30 ppm, 2H, m; 7.06 ppm, 5H, m; 6.85 ppm, 2H,m; 6.76 ppm, 1H, m; 6.62 ppm, 2H, m; 5.79 ppm, 1H, m; 4.13 ppm, 1H, s;3.84 ppm, 1H, m; 3.47 ppm, 1H, m; 1.12 ppm, 9H, s; 0.84 ppm, 9H, s; 0.01ppm, 6H, d, J=4.39 Hz.

Procedure 113

At room temperature a solution of NaOMe (5 mL, 0.5 M solution in MeOH)was added to the 4:1 diastereomeric mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(801 mg, 1.22 mmol). The reaction mixture was stirred for 15 minutes,MeOH was removed then the residue dissolved in EtOAc (50 mL) andtransferred to a separation funnel. HCl (20 mL, 1.0 N solution) wasadded and the EtOAc layer was separated. The aqueous layer was extractedwith EtOAc (2×10 mL) and the combined organic layers were dried overNa₂SO₄, filtered and concentrated to yield(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white foam (578 mg, 87% yield). LCMS: RT=1.987 min [M+H] 546.35(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

At rt to a solution of(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(578 mg, 1.06 mmol) in DMF (10 mL) was added K₂CO₃ (800 mg, 5.80 mmol)and the slurry was stirred vigorously. 2-Iodopropane (220 mg, 1.27 mmol)was added and the reaction mixture was stirred at rt for 16 h. Thereaction mixture was diluted with ether (50 mL), washed successivelywith 10% LiCl (2×20 mL) and water (20 mL). The organic portion was driedover Na₂SO₄, filtered and concentrated to yield(R)-N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a pale orange foam (780 mg, 100% yield).

The diastereomeric mixture of(R)-N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(,1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(780 mg, 1.06 mmol crude) was separated by Chiral preparative HPLCchiralpak AD 20μ column, 5×50 cm, eluting with 30% IPA/Heptane with flowrate 50 mL/min.

(R)-N-((S)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 17 min and isolated as a colorless oil(101 mg, yield 16%). LCMS: RT=2.128 min [M+H] 588.38 (Phenomenex LunaC18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); Chiral HPLC:RT=4.35 min, ee 100% (Diacel Chiralpak AD 10μ column, 4.6×250 mmisocratic elution with IPA (20%) and heptane; 1 mL/min, monitoring at254 nm).

(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 39 min and isolated and was isolatedas a colorless oil (398 mg, yield 64%). LCMS: RT=2.138 min [M+H] 588.38(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; mL/min, monitoring at 220 nm); ChiralHPLC: RT=9.98 min, ee 100% (Diacel Chiralpak AD 10μ column, 4.6×250 mmisocratic elution with IPA (20%) and heptane; 1 mL/min, monitoring at254 nm) NMR: 400 MHz ¹H (CDCl₃) 7.08 ppm, 5H, m; 6.84 ppm, 2H, d, J=7.47Hz; 6.77 ppm, 2H, d, J=7.47 Hz; 6.63 ppm, 2H, m; 5.79 ppm, 1H, t,J=52.95 Hz; 4.33 ppm, 1H, m; 4.15 ppm, 1H, s; 3.92 ppm, 1H, d, J=12.30Hz; 3.48 ppm, 1H, d, J=12.30 Hz; 1.22 ppm, 3H, d, J=6.15 Hz; 1.18 ppm,3H, d, J=5.71 Hz; 1.14 ppm, 9H, s.

To a solution of(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(398 mg, 0.678 mmol) in MeOH (1.5 mL) was added HCl (1.5 mL, 4 Msolution in dioxane) and the reaction mixture was stirred for 30 min.The reaction mixture was diluted with ether (50 mL) and the organiclayer was washed with sat. NaHCO₃ (20 mL), dried over Na₂SO₄, filteredand concentrated to give(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamineas a colorless oil (334 mg, 100% yield). LCMS: RT=1.76 min [M−NH₂]467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=3.04 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.15 ppm, 3H, m;6.99 ppm, 4H, m; 6.89 ppm, 1H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm,2H, d, J=6.15 Hz; 5.87 ppm, 1H, m; 4.42 ppm, 1H, m; 3.47 ppm, 2H, s;1.27 ppm, 6H, dd, J=7.91, 6.15 Hz.

An alternative route used to prepare(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanaminewas as follows:

Procedure 114

The diastereomer mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(1.14 g, 1.73 mmol) was separated by Chiral preparative HPLC chiralpakAD 20μ column, 5×50 cm, eluting with 30% IPA/Heptane with flow rate 50mL/min.

(R)-N-((S)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 19 min (114 mg, yield 10%). LCMS:RT=2.45 min [M+H] 660.41 (Phenomenex Luna C18 column, 4.6×30 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm).

(R)-N-((R)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 36 min (634 mg, yield 56%). LCMS:RT=2.41 min [M+H] 660.39 (Phenomenex Luna C18 column, 4.6×30 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm); Chiral HPLC: RT=8.54 min, ee 100% (DiacelChiralpak AD 10 column, 4.6×250 mm isocratic elution with IPA (20%) andheptane; 1 mL/min, monitoring at 254 nm) NMR: 400 MHz ¹H (CDCl₃) 7.03ppm, 5H, m; 6.84 ppm, 2H, m; 6.74 ppm, 1H, d, J=8.79 Hz; 6.66 ppm, 1H,dd, J=8.13, 1.98 Hz; 6.61 ppm, 2H, m; 5.76 ppm, 1H, m; 4.12 ppm, 1H, s;3.90 ppm, 1H, d, J=12.74 Hz; 3.46 ppm, 1H, d, J=12.30 Hz; 1.11 ppm, 9H,s; 0.84 ppm, 9H, s; 0.01 ppm, 6H, d, J=4.83 Hz.

(R)-N-((R)-1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared from(R)-N-((R)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 112 in quantitative yield. LCMS: RT=1.998 min[M+H] 546.28 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). HPLC: RT=3.83 min, Purity 98% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.61 ppm, 1H, s;7.40 ppm, 1H, dd, J=8.13, 1.98 Hz; 7.13 ppm, 3H, m; 6.99 ppm, 1H, dd,J=10.33, 8.57 Hz; 6.84 ppm, 3H, m; 6.68 ppm, 2H, m; 6.61 ppm, 1H, m;5.85 ppm, 1H, tt, J=52.95, 2.64 Hz; 4.30 ppm, 1H, s; 4.02 ppm, 1H, d,J=12.30 Hz; 3.50 ppm, 1H, d, J=12.30 Hz; 1.24 ppm, 9H, s.

(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared from(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 6 in 78% yield. LCMS: RT=2.17 min [M+H] 588.17(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm) HPLC:RT=4.20 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.16 ppm, 3H, m; 7.10 ppm,2H, m; 6.87 ppm, 4H, m; 6.70 ppm, 2H, m; 5.86 ppm, 1H, m; 4.41 ppm, 1H,m; 4.31 ppm, 1H, s; 3.98 ppm, 1H, d, J=12.74 Hz; 3.56 ppm, 1H, d,J=12.74 Hz; 1.30 ppm, 3H, d, J=5.71 Hz; 1.25 ppm, 3H, d, J=6.15 Hz; 1.22ppm, 9H, s.

(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanaminewas prepared from(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 6 in 97% yield. LCMS: RT=1.83 min [M−NH₂]467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=3.17 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.16 ppm, 3H, m;7.01 ppm, 3H, m; 6.92 ppm, 2H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm,2H, d, J=7.03 Hz; 5.86 ppm, 1H, m; 4.41 ppm, 1H, m; 3.49 ppm, 2H, s;1.25 ppm, 6H, m.

Procedure 115

At rt, to a solution of(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine(25 mg, 0.05 mmol) in anhydrous DCM (0.5 mL) was added pyridine (1 drop)and 2,2,3,3,3-pentafluoropropanoic anhydride (19 mg, 0.08 mmol). Theresulting solution was stirred for 5 min, diluted with MeOH (0.5 mL) andpurified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with10-90% MeOH/H₂O over 10 minutes containing 0.1% TFA; 40 mL/min,monitoring at 220 nm).(R)-2,2,3,3,3-pentafluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)propanamide(Example 307) was isolated as a colorless oil (7 mg, 21% yield) at aretention time of 11.84 min. LCMS: RT=2.19 min [M+H] 630.32 (PhenomenexLuna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.21 min,Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220nm) NMR: 400 MHz ¹H (CDCl₃) 7.25 ppm, 3H, m; 7.03 ppm, 1H, t, J=8.0 Hz;6.86-6.97 ppm, 4H, m; 6.66 ppm, 2H, d, J=8.0 Hz; 6.58 ppm, 2H, d, J=8.0Hz; 5.87 ppm, 1H, d, J=57.8 Hz; 4.32 ppm, 1H, sept, J=8.0 Hz; 3.93 ppm,1H, d, J=12.0 Hz; 3.68 ppm, 1H, d, J=12.0 Hz; 1.28 ppm, 3H, d, J=8.0 Hz;1.22 ppm, 3H, d, J=8.0 Hz.

Example 308

(R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)ureaProcedure 116

To a suspension of sodium hydride (60% in mineral oil, 3.7 g, 92 mmol)in dry DMF (32 mL) under nitrogen was added dropwise diisopropylmalonate (16 mL, 84 mmol) and the temperature was maintained below 0° C.On cessation of hydrogen evolution, 1,3-dibromo-2,2-dimethoxypropane(11.0 g, 42 mmol) was added at rt and the reaction mixture was heated at140° C. for 24 h. The cooled mixture was poured into saturated ammoniumchloride (100 mL) and extracted with hexane (3×75 mL). The combinedorganic extracts were washed with water (100 mL), sat. NaHCO₃ (50 mL),dried over magnesium sulfate and the solvent was evaporated to give17.42 g of pale yellow oil. Distillation of the residue through Vigreuxcolumn with an air condenser and further purification by an Analogixsilica column (12 g, 20% ethyl acetate in hexane) afforded diisopropyl3,3-dimethoxycyclobutane-1,1-dicarboxylate (6.2 g, 51% yield). LCMS:RT=3.26 min, No parent ion (Phenominex, Luna C18, 4.6×50 mm, 4 mingradient from 10% methanol, 90% water, 0.1% TFA to 90% methanol, 10%water, 0.1% TFA); ¹H NMR (500 MHz, CDCl₃) δ ppm 5.06 (2H, dq), 3.15 (6H,s), 2.69 (4H, s), 1.24 (12H, d, J=6.0 Hz); ¹³C NMR (126 MHz, CDCl₃) δppm 170.34 (2C, s), 98.50, 69.03 (2C, s), 48.59 (2C, s), 45.01, 39.63(2C, s), 21.47 (4C, s).

Procedure 117

A solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate(2.2 g, 7.63 mmol) in HCl (6 N, 6 mL) was heated at 155-160° C. undermicrowave irradiation for 60 min. The reaction mixture was diluted withether (150 mL) and vigorously stirred over the weekend. The ether layerwas dried with MgSO₄, filtered and concentrated to give3-oxocyclobutanecarboxylic acid (1.0 g, 118% yield) as a brown solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 10.80 (1H, br. s.), 3.43-3.51 (2H, m),3.26-3.40 (3H, m); ¹³C NMR (126 MHz, CDCl3) δ ppm 203.14, 180.17, 51.64(2C, s), 27.32 (1C, s).

Procedure 118

To a solution of 3-oxocyclobutanecarboxylic acid (3.34 g, 29.2 mmol) indichloromethane (29 mL) at 0° C. was added oxalyl chloride (19.0 mL,38.0 mmol) followed by DMF (0.057 mL, 0.731 mmol). The reaction mixturewas stirred for 2 h at room temperature. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved indichloromethane (15 mL). At 0° C., to the resulting solution was addedsodium azide (3.23 g, 49.7 mmol) in water (7 mL) followed bytetrabutylammonium bromide. The reaction mixture was vigorously stirredfor 2 h. The aqueous phase was separated and extracted withdichloromethane (2×40 mL). The combined organic portions were dried overMgSO₄, filtered rapidly and benzyl alcohol (30.4 ml, 292 mmol) was addedand the solvent volume was reduced under reduced pressure. The reactionmixture was heated at 95° C. for 1 h. Benzyl alcohol was removed underreduced pressure and the residue oil was purified by ISCO flashchromatography (80 g column, hexane/ethyl acetate) to give benzyl3-oxocyclobutylcarbamate as a pale yellow solid (693 mg, 11% yield).HPLC: RT=1.16 min, 90% pure (Phenomenex, Onyx C18, 4.6×100 mm, 2 mingradient from 10% MeCN, 90% water, 0.1% TFA to 90% MeCN, 10% water, 0.1%TFA); LCMS: RT=2.37 min, 75% purity, [M+H] 220.1 (Phenominex, Luna C18,4.6×50 mm, 4 min gradient from 10% methanol, 90% water, 0.1% TFA to 90%methanol, 10% water, 0.1% TFA); ¹H NMR (500 MHz, CDCl₃) δ ppm 7.32-7.38(5H, m), 5.27 (1H, d, J=3.3 Hz), 5.12 (2H, s), 4.33 (1H, d, J=5.5 Hz),3.40 (2H, dd, J=13.2, 6.6 Hz), 3.08 (2H, d, J=14.3 Hz). ¹³C NMR (101MHz, CDCl₃) δ ppm 204.50, 155.87, 136.06, 128.56 (2C, s), 128.28, 128.13(2C, s), 66.97, 54.59 (2C, s), 37.08.

Procedure 119

To a solution of benzyl 3-ocyclobutylcarbamate (2.58 g, 11.77 mmol) indichloromethane (23.5 mL) at 0° C. to −5° C. was added dropwise DAST(4.66 mL, 35.3 mmol). The reaction mixture was stirred for 4.5 h at roomtemperature, then diluted with sat. NaCl at 0° C. and the aqueous layerswere extracted with dichloromethane (3×50 mL). The combined organiclayers were dried over MgSO4, filtered and concentrated. The resultingoil was purified by ISCO flash chromatography (120 g column, hexanes toethyl acetate) to yield benzyl 3,3-difluorocyclobutylcarbamate (1.7 g,yield 60%). LCMS: RT=2.95 min [M+H] 242.1 (Phenomenex Luna C18 column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1%TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR (500 MHz, CDCl₃) δ ppm7.30-7.41 (5H, m), 5.10 (2H, br. s.), 4.99 (1H, br. s.), 4.04-4.16 (1H,m), 2.90-3.04 (2H, m), 2.42-2.56 (2H, m); ¹³C NMR (126 MHz, CDCl₃) δ ppm155.52, 136.07, 128.58 (2C, s), 128.30, 128.18 (2C, s), 66.97,42.72-43.57 (1C, m), 35.71-36.66 (2C, m), the triplet for thedifluorocarbon signal did not rise above baseline; ¹⁹F NMR (471 MHz,CDCl₃) δ ppm −84.90 (1F, d, J=195.8 Hz), −97.62 (1F, d, J=201.5 Hz).

Procedure 120

To a solution of benzyl 3,3-difluorocyclobutylcarbamate (1.86 g, 7.71mmol) in methanol (49 mL) and chloroform (2 mL) was added 10% palladiumon carbon (0.41 g, 0.39 mmol) and the slurry was subjected to balloonhydrogenation overnight. The reaction mixture was filtered, washed withmethanol and HCl (1.0 M) in ether (1 mL) and the filtrate concentrated.The residue was triturated with ether, filtered, washed with ether anddried to give 3,3-difluorocyclobutanamine hydrochloride as a pale yellowsolid (1.01 g, 92% yield). ¹H NMR (400 MHz, DMSO-D6). δ ppm 8.48 (m,3H), 3.60-3.69 (m, 1H), 2.72-3.02 (m, 4H); ¹⁹F NMR (376 MHz, DMSO-D6) δppm −81.57 (1F, d, J=189.6 Hz), −97.13 (1F, ddd, J=198.8 Hz, 18.5 Hz).

(R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea(Example 308) was prepared as described in Procedure 10. LCMS: RT=2.003min [M+H] 639 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm). HPLC: RT=4.10 min, 100% purity (Phenomenex Luna C18 column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2%PPA; 4 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz, Solvent) δ ppm2.33-2.44 (m, 2H), 2.86-2.97 (m, J=15.25, 7.83, 7.70, 3.30 Hz, 2H),3.63-3.72 (m, 3H), 3.74-3.85 (m, 1H), 3.93-4.03 (m, 1H), 4.09 (d, J=7.15Hz, 1H), 6.62-6.69 (m, 1H), 6.70-6.78 (m, 3H), 7.00 (ddd, J=11.13, 8.11,3.30 Hz, 1H), 7.10-7.21 (m, 3H), 7.29-7.40 (m, 3H).

Example 309

(R)-N-(1-(3-cyclopropyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide

Procedure 121

To a mixture of(S)-N-(1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide,prepared as described in Procedures 3, 62, 5, 6 and 7, (50 mg, 0.07mmol), (50 mg, 0.07 mmol), cyclopropylboronic acid (6 mg, 0.07 mmol),palladium (II) acetate (1 mg, 0.004 mmol) and tricyclohexylphosphine (2mg, 0.007 mmol) in toluene (2 mL) was added K₃PO₄ (0.072 mL, 0.22 mmol).The reaction mixture was heated at 100° C. under microwave irradiationfor 15 min. The reaction mixture was filtered, concentrated and theresulting residue was purified by preparative HPLC (Sunfire-S5-C18 18×50mm column, eluting with 10-90% MeOH/H₂O gradient over 8 min, with flowrate 20 mL/min and UV detection at 220 nm) to yield(R)-N-(1-(3-cyclopropyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 309, 14 mg, 30% yield). LCMS: RT=4.37 min [M+H] 656.38 (WatersSunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (500 MHz,CDCl₃) δ ppm 7.90 (1H, dd, J=6.60, 1.92 Hz), 7.81-7.84 (1H, m),7.22-7.30 (5H, m), 7.16 (2H, t, J=7.56 Hz), 6.93-7.00 (4H, m), 6.77-6.81(1H, m), 6.68 (2H, d, J=7.42 Hz), 6.62 (1H, s), 6.54 (1H, dd, J=6.87,2.47 Hz), 5.88 (1H, t, J=52.73 Hz), 4.08 (1H, d, J=13.20 Hz), 3.66 (1H,d, J=13.20 Hz), 2.03 (1H, ddd, J=13.75, 8.52, 5.22 Hz), 0.92-0.96 (2H,m), 0.52-0.56 (1H, m), 0.43-0.47 (1H, m).

Example 310

(R)-4-fluoro-N-(1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 122

To a solution of[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (8 mg, 0.01 mmol) in NMP (0.5 mL) was added isobutylzinc(II)bromide in THF (0.5 M, 0.7 mL, 0.35 mmol) followed by(S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine,prepared as described Procedure 62, 5 and 6, (50 mg, 0.11 mmol) inanhydrous THF. The reaction mixture was heated at 75° C. overnight. Thereaction mixture was diluted with EtOAc and the organic layer was washedwith sat. NH₄Cl, dried over Na₂SO₄ and concentrated to yield(R)-1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine.LCMS: RT=3.62 min [M−NH₂] 417 (Waters Sunfire-S5-C18 4.6×50 mm, elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm).

Following Procedure 7,(R)-4-fluoro-N-(1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 310) was prepared (13 mg, 18% yield). LCMS: RT=4.68 min [M+H]624.33 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H₂Oover 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹HNMR (500 MHz, CDCl₃) δ ppm 7.89 (1H, dd, J=6.46, 2.06 Hz), 7.82 (1H,ddd, J=8.45, 4.61, 2.34 Hz), 7.37 (1H, s), 7.22-7.30 (6H, m), 7.16 (2H,t, J=7.56 Hz), 6.98 (1H, t, J=8.80 Hz), 6.87-6.90 (1H, m), 6.83 (1H, dd,J=6.74, 2.61 Hz), 6.71 (1H, s), 6.69 (2H, d, J=7.15 Hz), 4.07 (1H, d,J=12.92 Hz), 3.78 (1H, d, J=13.20 Hz), 2.47-2.52 (1H, m), 2.40-2.45 (1H,m), 1.80 (1H, dt, J=13.54, 6.84 Hz), 0.85 (6H, dd, J=9.62, 6.60 Hz).

Example 311

(S)-4-fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 123

To a suspension of NaH (60% in oil, 0.24 g, 6 mmol) in dry THF (25 mL)under nitrogen was added 15-crown-5 (0.06 g). The suspension was cooledin an ice bath. Bis(3-(trifluoromethoxy)phenyl)methanone (2.10 g, 6mmol) and diethyl benzylphosphonate (1.37 g, 6 mmol) were dissolved inTHF (12 mL) and added to the suspension. The reaction mixture wasstirred at ice bath temperature for 15 min, allowed to warm to rt andstirred overnight. The reaction mixture was poured into water andextracted with ether (2×). The combined ether layers were washed with10% NaHSO₃, sat. NaCl, dried over K₂CO₃, filtered and purified by ISCOusing a gradient of 0-4% EtOAc/hexanes as eluent to give3,3′-(2-phenylethene-1,1-diyl)bis((trifluoromethoxy)benzene) as acolorless oil (1.34 g, 53% yield). ¹H NMR (400 MHz, CDC₃) δ ppm 7.33 (m,2H), 7.2-7.1 (m, 8H), 7.04 (s, 1H), 7.0-6.97 (m, 3H).

Procedure 124

A mixture of3,3′-(2-phenylethene-1,1-diyl)bis((trifluoromethoxy)benzene) (1.30 g,3.06 mmol), R,R-MnCl (salen) (0.40 g, 0.64 mmol),4-phenylpyridine-N-oxide (0.22 g, 1.27 mmol) in CH₂Cl₂ (30 mL) wascooled in an ice bath. A cold bleach (6.2% NaOCl in water, 11.54 g, 9.52mmol) was added and the reaction mixture was allowed to warm to rt andstirred for 48 h. The dark brown reaction mixture was diluted withCH₂Cl₂ and filtered through celite. The organic layer was separated,washed with water, sat. NaCl, dried over MgSO₄, filtered andconcentrated to yield a dark brown oil. The resulting oil was purifiedby ISCO using a gradient of 0-7% EtOAc/hexanes to give(S)-3-Phenyl-2,2-bis(trifluoromethoxy)phenyl)oxirane as a light yellowoil (0.96 g, 71% yield). HPLC: RT=4.68 min (Phenomenex Luna C18 5 ucolumn, eluting with 10-90% MeOH/H₂O containing 0.1% phosphoric acidover a 4 minute gradient, monitoring at 220 nm). ¹H NMR (400 MHz, CDCl₃)δ ppm 7.4-7.0 (m, 13H), 4.32 (s, 1H).

Procedure 125

To a suspension of sodium azide (65 mg, 1 mmol) in toluene (9.1 mL)cooled at −78° C. was added 1 M ethylaluminum dichloride (0.91 mL, 0.91mmol). The reaction mixture was stirred for 4 h at −78° C.(S)-3-Phenyl-2,2-bis(trifluoromethoxy)phenyl)oxirane (0.2 g, 0.45 mmol)was dissolved in toluene (0.5 mL) and added dropwise via syringe. Thereaction mixture was stirred at −78° C. for min and then allowed to warmto rt and stirred overnight. The reaction mixture was diluted with EtOAc(5 mL) and NaN₃ (1 g) and water (1 mL) were added and stirred for 1 h.The resulting mixture was filtered through a pad of sodium sulfate andthe filtrate was concentrated to a yellow oil. The residue was purifiedby ISCO using a gradient of 0-30% EtOAc/hexane as eluent to give(S)-2-azido-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol as alight yellow oil (69 mg, 31% yield). HPLC: RT=4.438 min (Phenomenex LunaC18 5 u column, eluting with 10-90% MeOH/H₂O containing 0.1% phosphoricacid over a 4 minute gradient, monitoring at 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.5-7.0 (m, 13H), 5.63 (d, 1H), 2.35 (d, 1H).

Procedure 126

A slurry of(S)-2-azido-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (64 mg,0.132 mmol) and 10% Pd on C (40 mg) in methanol (2 mL) was subjected toballoon hydrogenation overnight at rt. The reaction mixture was filteredthrough celite and the filtrate was concentrated to give(S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol as alight yellow oil (53 mg, 87% yield). HPLC: RT=3.40 min (Phenomenex LunaC18 5 u column, eluting with 10-90% MeOH/H₂O containing 0.1% phosphoricacid over a 4 minute gradient, monitoring at 220 nm). LCMS: [M+H] 458.1(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

Procedure 127

A solution of(S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg,0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalyticamount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. Thereaction mixture was diluted with EtOAc and washed successively with 1 NHCl, 1 N NaOH, sat. NaCl, dried over MgSO₄, filtered and concentrated.The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5μcolumn, 30×100 mm eluting with 50-100% MeOH (90% in H₂O, 0.1% TFA)gradient over 10 min with flow rate 40 mL/min and UV detection at 220nm.(S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC:RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90%aqueous methanol containing 0.1% phosphoric acid over a 4 minutegradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz, CDCl₃) δ ppm8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).

Example 312

(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)butanamideProcedure 128

To a solution of 4,4,4-trifluorobutyric acid (13 mg, 0.09 mmol) in DCM(0.8 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (52 mg, 0.1 mmol),(R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine(40 mg, 0.08 mmol), followed by NMM (28 μl, 0.25 mmol). The reactionmixture was stirred at room temperature for 16 h, then another 16 h at60° C. The reaction mixture was diluted with EtOAc (10 mL) and theorganic layer was washed with H₂O, dried over MgSO₄, filtered andconcentrated. The residue was purified by preparative HPLC PhenomenexLuna C18 column, 30×50 mm eluting with 10-90% ACN/H₂O over 10 minutescontaining 0.1% TFA; 40 mL/min, monitoring at 220 nm; 40-100% ACN (90%in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UVdetection at 220 nm.(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy)phenyl)-2-phenylethyl)butanamide(Example 312) was isolated as a lyophillate (27 mg, 55% yield). LCMS:RT=2.15 min [M+H] 608.2 (2 min Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm); HPLC: RT=3.79 min, Purity 100%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% ACN/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR(400 MHz, CDCl₃) δ ppm 1.18 (d, J=6.05 Hz, 3H), 1.24 (d, J=6.05 Hz, 3H),2.34-2.48 (m, 2H), 2.51-2.61 (m, 2H), 3.79 (d, J=13.19 Hz, 1H), 3.98 (d,J=13.19 Hz, 1H), 4.29-4.39 (m, 1H), 6.12-6.44 (m, 1H), 6.67-6.82 (m,4H), 6.91-7.07 (m, 4H), 7.10-7.19 (m, 3H), 8.29 (s, 1H).

Example 313

Ethyl6-(4-(2-(3-cyclopentylureido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenoxy)hexanoateProcedure 129

To an oven-dried 3-necked 10 mL round-bottom flask under nitrogen wasadded1-cyclopentyl-3-(2-(4-hydroxyphenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)urea,prepared as described in Procedure 11, 6, 2 and 59, (50 mg, 0.1 mmol),triphenylphosphine (34 mg, 0.1 mmol), ethyl 6-hydroxyhexanoate (17 mg,0.1 mmol) and dry THF (0.5 mL). The reaction mixture was cooled in anice-methanol bath and diethylazodicarboxylate (23 mg, 0.13 mmol) wasadded via syringe. The reaction was allowed to warm to rt and stirredovernight. The reaction mixture was concentrated in vacuo and purifiedby ISCO silica gel chromatography using a gradient of 5-25%EtOAc/hexanes as eluent to yield ethyl6-(4-(2-(3-cyclopentylureido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenoxy)hexanoate(Example 313) was isolated as a white solid (43 mg, 61% yield). HPLC:RT=4.69 minutes (Phenomenex Luna C18 column 4.6×50 mm eluting with10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minutegradient monitoring at 220 nm). LC/MS [M+H] 711.3 (Phenomenex Luna C185μ column 4.6×30 mm eluting with 10-90% aqueous methanol containing 0.1%TFA over a 4 minute gradient monitoring at 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.33 (t, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.12 (d,J=7.9 Hz, 2H), 7.07 (s, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.56 (d, J=8.8 Hz,2H), 4.10 (q, J=7.1 Hz, 2H), 3.86t, J=6.1 Hz, 2H), 3.68 (s, 1H), 3.62(t, J=6.6 Hz, 1H), 2.30-2.27 (m, 2H), 1.82-1.14 (m, 17H), 1.23 (t, J=7.1Hz, 3H).

Example 314

1-(2,2-difluorocyclohexyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureaProcedure 130

At 0° C. to a solution of benzyl 2,5-dioxocyclopentanecarboxylate (2.58g, 10.35 mmol) in MeOH (20 mL) was added 2-aminocyclohexanol (1.25 g,10.87 mmol). The reaction mixture was stirred at room temperature for 18h and quenched with 0.25 N HCl (8 mL). MeOH was removed under vacuum andthe aqueous layer was extracted with CH₂Cl₂ (4×10 mL). The combinedorganic layers were washed with sat. NaCl (20 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by ISCOchromatography (40 g column) using hexanes/EtOAc (0-5% over 15 min,5-10% over 7 min) to give benzyl 2-hydroxycyclohexylcarbamate as a lightyellow solid at a retention time of 11-13 min (2.15 g, 83% yield). HPLC:RT=2.83 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.33 ppm, 5H, m; 5.16 ppm,1H, m; 5.09 ppm, 2H, s; 3.95 ppm, 1H, s; 3.68 ppm, 1H, m; 1.54 ppm, 8H,m.

A mixture of CrO₃ (0.70 g) in concentrated H₂SO₄ (0.61 mL) was dilutedwith H₂O to the volume of 6 mL. To a solution of benzyl2-hydroxycyclohexylcarbamate (1.60 g, 6.43 mmol) in acetone (5.4 mL) at0° C. was added Jones Reagent (5.51 mL, 1.17 M, 6.43 mmol) dropwise over5 min. The reaction mixture was stirred at room temperature for 1.5 h,quenched with 20% aq. K₂CO₃ to pH=8. The aqueous layer was extractedwith EtOAc (3×15 mL). The combined organic layers were washed with sat.NaCl (20 mL), dried over Na₂SO₄, filtered and concentrated. The resultedcrude yellow oil was purified by ISCO chromatography (40 g column) usinghexanes/EtOAc (0-30% over 8 min, 30-45% over 10 min) to give benzyl2-oxocyclohexylcarbamate as a colorless oil at a retention time of8.5-11 min (1.26 g, 79% yield). HPLC: RT=2.69 min, Purity 99%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400MHz ¹H (CDCl₃) 7.33 ppm, 5H, m; 5.76 ppm, 1H, s; 5.11 ppm, 2H, m; 4.27ppm, 1H, m; 2.65 ppm, 1H, dd, J=6.60, 2.75 Hz; 2.52 ppm, 1H, m; 2.38ppm, 1H, m; 2.13 ppm, 1H, m; 1.89 ppm, 1H, m; 1.77 ppm, 1H, m; 1.64 ppm,1H, m; 1.42 ppm, 1H, m.

At room temperature to a solution of benzyl 2-oxocyclohexylcarbamate(294 mg, 1.19 mmol) in DCM (5 mL) was added DAST (0.5 mL, 3.92 mmol).The reaction mixture was stirred for 18 h, cooled to 0° C. and quenchedby addition of sat. NaCl (1 mL). The aqueous phase was separated andextracted with DCM (3×8 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The residue was purified by ISCOchromatography (12 g column) using hexanes/EtOAc (0-30% over 15 min,30-45% over 10 min) to give benzyl 2,2-difluorocyclohexylcarbamate as abrown oil at a retention time of 7-10 min (272 mg, 85% yield). HPLC:RT=3.03 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm). NMR: 400 MHz ¹H (CDCl₃) 7.34 ppm, 5H, m; 5.12ppm, 2H, m; 4.99 ppm, 1H, d, J=8.35 Hz; 3.93 ppm, 1H, m; 2.18 ppm, 1H,m; 2.04 ppm, 1H, m; 1.77 ppm, 2H, m; 1.46 ppm, 4H, m.

A solution of benzyl 2,2-difluorocyclohexylcarbamate (38 mg, 0.14 mmol)in 6 N HCl (2 mL) was heated at 100° C. for 2 h. The cooled reactionmixture was extracted with ether (3×1 mL) and the combined organiclayers were concentrated to give 2,2-difluorocyclohexanaminehydrochloride as a light brown solid (23 mg, 96% crude).

1-(2,2-Difluorocyclohexyl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea(Example 314) was prepared as described in Procedure 12 (43 mg, 60%yield). LC/MS: RT=4.07 min [M+H] 587.3 (Phenomenex Luna C18 column,4.6×50 mm eluting with 10-90% MeCN/H₂O over 4 minutes containing 0.1%NH₄OAc; 4 mL/min, monitoring at 220 nm).

Example 315

(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzothioamideProcedure 131

To a stirred solution of(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(105 mg, 0.17 mmol), prepared as described in Procedure 3, 4, 5, 6 and7, in toluene (5.2 mL) was added Lawesson's reagent (83 mg, 0.20 mmol).The reaction mixture was heated at 110° C. After 8 h, the reactionmixture was concentrated and the residue was purified by ISCO columnchromatography (EtOAc/hexane 0-100%, SiO₂) to provide(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzothioamide(Example 315, 89 mg, 83% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃)δ ppm 7.92 (s, 1H), 7.74-7.72 (m, 1H), 7.68-7.66 (m, 1H), 7.22-6.86 (m,11H), 6.72 (d, J=5Hz, 2H), 5.92-5.70 (m, 1H), 4.36 (d, J=15 Hz, 1H),3.82 (d, J=10 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ ppm 195 (C═S); LC/MS:RT=4.393 min [M+H] 632.4 (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeCN/H₂O over 4 minutes containing 0.1% NH₄OAc; 4 mL/min,monitoring at 220 nm).

Example 316

(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,2,2-trifluorovinyloxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 132

At −78° C. under argon, to a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(31 mg, 0.046 mmol), prepared as described in Procedure 3, 4, 5, 6, 7,59 and 68, in dry THF (0.7 mL) was added nBuLi (2.5 M in hexane, 0.25mL, 0.625 mmol) dropwise. The reaction mixture was allowed to warm to−5° C. over 1.5 h period. After stirring for total 2 h, the reactionmixture was quenched by addition of sat. NH₄Cl and the aqueous phase wasextracted with EtOAc and the organic layer was concentrated. Theresulting residue was purified by reverse phase HPLC to give puredesired product (7 mg, 23% yield). LC-MS: RT=4.19 min [M+H] 654.3(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, Methanol-d₄) δ ppm 8.85 (m, 1H), 8.00 (m, 2H), 7.47 (t, J=8.8Hz, 1H), 7.22 (m, 1H), 7.15 (t, J=7.7 Hz, 2H), 7.07 (m, 1H), 7.01-6.94(m, 2H), 6.90 (m, 1H), 6.88-6.83 (m, 2H), 6.75 (m, 1H), 4.01 (AB, J=12.9Hz, 2H), 1.27, 1.21 (d, J=6.1 Hz, 6H).

Example 317

(R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 133

Following Procedure 14,(R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-2-methylpropane-2-sulfinamidewas prepared (1.9 g, 92% yield). The two diastereomers were separatedvia chiral AD column (20% isopropanol/heptanes//0.1% DEA) to give(R)-N-((S)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-2-methylpropane-2-sulfinamide(1.02 g) as the fast eluting isomer and(R)-N-((R)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-2-methylpropane-2-sulfinamide(0.88 g) as the slow eluting isomer.(R)-N-((R)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-2-methylpropane-2-sulfinamide:LCMS: RT=4.08 min [M+H] 548.2 (Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm).

At 0° C. under argon, to a solution of(R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-3-(2,2,2-trifluoroethyl)urea(40 mg, 0.070 mmol), prepared as described in Procedure 6 and 10, in drytoluene (1 mL) was added diethyl Zinc (1.0 M in hexane, 1.2 mL, 1.2mmol), followed by dropwise addition of diiodomethane (0.2 mL). Thereaction mixture was gradually warmed to 110° C., and heated at 110° C.for 1 h. After cooling, 1 N HCl was added and the reaction mixture wasstirred at room temperature for 5 min. The reaction mixture wasextracted with EtOAc and the organic layer was washed with H₂O, sat.NaHCO₃, sat. NaCl, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 ucolumn eluting with 50-100% MeOH in H₂O with 0.1% TFA, 40 mL/min,monitoring at 220 nm) to give(R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea(Example 317) as white solid (13 mg, yield 32%). LCMS: RT=3.26 min [M+H]583.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.55 (d, J=6.6 Hz, 1H), 7.46 (m, 1H),7.12 (t, J=9.3 Hz, 1H), 6.94-6.85 (m, 3H), 5.84 (tt, J=52.8, 2.8 Hz,1H), 5.61 (br, s, 1H), 4.78 (br, t, J=6.1 Hz, 1H), 3.69 (m, 2H), 2.31(m, 2H), 0.36 (m, 3H), 0.00 (m, 2H).

Example 318

(R)-methyl3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate

Procedure 134

(R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoicacid was prepared as described in Procedure 3, 4, 5, 14, 6, 7 and 23 (32mg, 79% yield). LCMS: 2.03 min [M+H] 584.2 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz, CDCl₃) δ ppm3.70 (s, 2H), 6.18 (t, J=53 Hz, 1H), 6.97 (d, J=8.79 Hz, 1H), 7.08 (t,J=8.79 Hz, 2H), 7.14 (s, 1H), 7.19 (d, J=10.44 Hz, 1H), 7.34-7.50 (m,3H), 8.05-8.18 (m, 3H).

To a solution of(R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoicacid (32 mg, 0.055 mmol) in toluene (0.5 mL) was added DPPA (18 mg,0.066 mmol) and TEA (7 mg, 0.066 mmol). The reaction mixture was heatedat 100° C. for 1 h followed by the addition of MeOH and TEA. Thereaction was heated at 65° C. overnight. Excess K₂CO₃ was added and thereaction was heated to reflux for 3 h. The reaction mixture wasconcentrated and the resulting residue was purified by preparative HPLC(phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA)gradient over 12 min with flow rate 40 mL/min and UV detection at 220nm) to yield (R)-methyl3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate(Example 318) as a white solid (5 mg, 15% yield). LCMS: RT=3.92 min[M+H] 613.3 (4 min Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm). ¹H NMR (400 MHz, CDCl₃) ppm 3.74 (s, 3H), 3.87-4.11 (m, 2H),4.89 (m, 1H), 5.86 (t, 1H), 6.95 (d, 1H), 6.99-7.13 (m, 5H), 7.28-7.40(m, 3H), 8.09-8.16 (m, 1H), 8.26 (d, 1H), 8.94 (s, 1H).

Example 319

(R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoicacid Procedure 135

To a suspension of(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea(5.0 mg, 0.01 mmol), prepared as described in Procedure 3, 4, 5, 6 and12, in a 1:1 mixture of water and tert-butyl alcohol (100 μL) was added4-azido-2,3,5,6-tetrafluorobenzoic acid (2.3 mg, 0.01 mmol), followed bysodium ascorbate (1 M solution in H₂O, 100 μL) and CuSO₄.5H₂O (1 mg).The reaction mixture was stirred vigorously overnight in a sealed vial.The reaction mixture was diluted with H₂O and extracted with EtOAc (3×).The combined organic portions were concentrated and the residue wasdissolved in MeOH and purified by preparative HPLC (Phenoma OnyxMonolithic 10×100 mm; eluting with 10%-90% MeCN/H₂O with 0.1% TFA,monitoring at 220 nm) to provide(R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoicacid (Example 319, 5.7 mg, 78% yield). LC/MS: RT=3.610 min [M+H] 742.3(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% NH₄OAc; 4 mL/min, monitoring at 220 nm). ¹HNMR (500 MHz, MeOH-d₄) δ 8.02 (s, 1H), 7.10-6.79 (m, 11H), 6.53 (d,J=5Hz, 2H), 6.27-6.04 (m, 1H), 4.38-4.31 (m, 2H), 3.81 (d, J=15 Hz, 1H),3.73 (d, J=10 Hz, 1H).

Example 320

(R)-N-(1-(4-carbamoylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 136

To a suspension of(R)-4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoicacid (224 mg, 0.4 mmol), prepared as described in Procedure 3, 4, 5, 6,7, 56, 57 and 23, in dichloromethane (3 mL) was added triethyl amine (97μL, 0.70 mmol) followed by fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH) (138 mg, 0.5 mmol). The reaction mixture wasstirred for 18 h. The reaction mixture was concentrated and the residuewas purified by flash chromatography (40 g silica gel; 0-40% ethylacetate, hexane gradient over 14 min., 40 mL/min) to provide(R)-4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoylfluoride (127 mg, 56% yield). LCMS: RT=2.39 min [M+H] 644 (ChromolithPerformance 18e 4.6×100 mm column, 10-90% methanol, water with 0.1%trifluoroacetic acid gradient over 2 min, mL/min)

To a suspension of(R)-4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoylfluoride (20 mg, 0.03 mmol) in acetonitrile (1 mL) was added ammonia (7M in methanol, 20 μL, 0.14 mmol). The reaction mixture was stirred for24 h. The reaction mixture was concentrated and the residue was purifiedby flash chromatography (4 g silica gel; 0-100% ethyl acetate, hexanegradient over 14 min., 18 mL/min) to provide(R)-N-(1-(4-carbamoylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 320, 13 mg, 65% yield). LCMS: RT=1.81 min [M+H] 631 (ChromolithPerformance 18e 4.6×100 mm column, 50-90% methanol, water with 0.1%trifluoroacetic acid gradient over 2 min, 5 mL/min). ¹H NMR (400 MHz,CDCl₃) ppm 7.86 (1H, d, J=4.83 Hz), 7.77 (1H, dt, J=8.35, 2.20 Hz), 7.71(2H, d, J=8.35 Hz), 7.14-7.25 (3H, m), 7.08 (3H, t, J=7.47 Hz),6.85-6.90 (3H, m), 6.71 (1H, s), 6.63 (2H, d, J=7.03 Hz), 6.05 (1H, s),5.88 (1H, tt, J_(HH)=2.75 Hz, J_(HF)=53 Hz), 5.70 (1H, s), 3.86 (2H, dd,J=37.4, 13.2 Hz).

Example 321

N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamideProcedure 137

(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanaminewas prepared by the methods described in Procedure 3, 4, 5 and 6.5-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxylicacid was prepared as described in Journal of Medicinal Chemistry, 2006,49, 14, 4055. To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(60 mg, 0.14 mmol), in anhydrous DMF (1 mL) was added N-methylmorpholine(26 mg, 0.28 mmol), PyBrOP (73 mg, 0.14 mmol) and5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxylicacid (40 mg, 0.14 mmol). The resulting solution was stirred at rt for 16h. The resulting solution was diluted with MeOH (0.5 mL) and purified bypreparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90%MeOH/H₂O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at220 nm).(N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamide(Example 321, 3 mg, 3% yield) was isolated as a colorless oil at aretention time of 11.29 min. LCMS: RT=2.18 min [M+H] 689.45 (PhenomenexLuna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; mL/min, monitoring at 220 nm); HPLC: RT=4.14 min,Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220nm) NMR: 400 MHz ¹H (CDCl₃) Diastereomeric ratio is 1:1; 7.28-6.86 ppm,24H, m; 6.64 ppm, 1H, m; 6.61 ppm, 1H, m; 5.88 ppm, 2H, t, J=60.0 Hz;5.16 ppm, 2H, t, J=16.0 Hz; 3.94 ppm, 1H, d, J=12.0 Hz; 3.88 ppm, 1H, d,J=12.0 Hz; 3.75 ppm, 1H, d, J=12.0 Hz; 3.68 ppm, 1H, d, J=12.0 Hz; 3.61ppm, 2H, m; 3.40 ppm, 1H, dm, J=12.0 Hz; 3.33 ppm, 1H, dm, J=12.0 Hz.

Example 322

(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-(methoxymethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 138

(R)-N-(1-(4-(bromomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(prepared as described in Procedure 3, 4, 5, 6, 7, 56, 57, 100 and 32,24 mg, 0.035 mmol) was dissolved in 0.5 mL of methanol. To this solutionwas added sodium methoxide (25% by wt, 0.5 mL) and the reaction mixturewas stirred for 40 min. The reaction was quenched with 1.0 M HCl andextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate, filtered and concentrated. The resulting oil was purified byflash chromatography (4 g silica gel column, 0-100% EtOAc/hexanegradient over 11 min., flow rate 18 mL/min) to provide(R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-(methoxymethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 321) as a white solid (15 mg, 67% yield). LC/MS: RT=1.62 min[M+H] 642 (Chromolith Performance 18e 4.6×100 mm column, 50-90%acetonitrile, water with 0.1% trifluoroacetic acid gradient over 2 min,5 mL/min); ¹H NMR (400 MHz, CDCl₃) ppm 7.91 (1H, d, J=7.15 Hz),7.77-7.87 (1H, m), 7.08-7.44 (7H, m), 6.97-7.05 (2H, m), 6.92 (1H, d,J=8.79 Hz), 6.66-6.75 (3H, m), 5.87 (1H, tt, J_(HH)=2.75 Hz, J_(HF)=53Hz), 4.47 (2H, s), 4.09 (1H, d, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz),3.42 (3H, s).

Example 323A

(S)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideExample 323B

(R)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideProcedure 139

To a solution of 2-amino-4,4,4-trifluorobutanoic acid (239.0 mg, 1.52mmol)) in dioxane (6 mL) was added 10% Na₂CO₃, followed by(9H-fluoren-9-yl)methyl carbonochloridate (394.0 mg, 1.52 mmol). Thereaction mixture was stirred at 0° C. for 1 h, then at rt for 1 h. Thereaction mixture was poured into a mixture of ether and water. Theaqueous layer was treated with concentrated HCl, then extracted with3×EtOAc. The organic layers were combined and dried over MgSO₄ andconcentrated. The residue was purified by ISCO chromatography (10 gcolumn, eluting with 0-30% EtOAc/hexane containing 0.1% AcOH) to yield(9H-fluoren-9-yl)methyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamateas a white solid (260.0 mg, yield 45%). LCMS: RT=3.06 min [M+H] 380.2(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).

Procedure 140

To a solution of(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(31 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, inDCM (1 mL) was added (9H-fluoren-9-yl)methyl1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate (31 mg, 0.08 mmol),followed by PyBrOP and iPr₂NEt. The reaction mixture was stirred at rtfor 72 h and concentrated. The residue was purified by preparative HPLC(Axia column, 30×100 mm, 60-100% MeOH/H₂O with 0.1% TFA over 12 min,flow rate 40 mL/min, monitoring at 220 nm) to yield(9H-fluoren-9-yl)methyl4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamateas white solid (20 mg, 38% yield). LCMS: RT=4.5 min [M+H] 787.3(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). Thisdiastereomer mixture was separated by Chiralpak AD column eluting with10% MeOH/EtOH(1:1)/90% heptane with flow rate 20 mL/min.(9H-fluoren-9-yl)methyl(S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamatewas eluted at a retention time of 8.26 min and isolated as a white solid(10 mg). (9H-fluoren-9-yl)methyl(R)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamatewas eluted at a retention time of 12.97 min and isolated as a whitesolid (10 mg). The stereochemistry of (9H-fluoren-9-yl)methyl(S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamateand (9H-fluoren-9-yl)methyl(R)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamatewas assigned arbitrarily.

Procedure 141

To a solution of (9H-fluoren-9-yl)methyl(S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate(10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1mmol). The reaction mixture was stirred at rt for 1.5 h andconcentrated. The residue was purified by preparative HPLC (Axia column,30×100 mm, 30-100% MeOH/H₂O with 0.1% TFA over 12 min, flow rate 40mL/min, monitoring at 220 nm) to yield(S)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min[M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12(2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s),6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91(1H, d, J=13.14 Hz), 3.71 (1H, d, J=13.39 Hz), 2.66 (2H, m).(R)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 323B) was prepared in the same method here and isolated as awhite solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (PhenomenexLuna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m),6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H,m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of(S)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 323A) and(R)-2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 323B) was assigned arbitrarily.

Example 324

2-amino-3,3,3-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)propanamideProcedure 142

At 0° C. to a solution of 2-amino-3,3,3-difluoropropanoic acid (143 mg,0.1 mmol) in 1,4-dioxane (1.3 mL) was added 10% aqueous Na₂CO₃ (2.6 mL),followed by dropwise addition of benzyl carbonochloridate (170 mg, 0.1mmol) in 1,4-dioxane (2.6 mL). The reaction mixture was stirred at 0° C.for 1 h, then allowed to warm up rt and stirred at rt for 72 h. Thereaction mixture was concentrated and the residue was purified by prepHPLC (Phenomenex Luna AXIA 5μ 21.2×100 mm, 10%-90% ACN/H₂O containing0.1% TFA, flow rate 20 mL/min, gradient time 10 min) to yield2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoic acid as a whitesolid (108 mg, 76% yield). HPLC: RT=2.64 min [M+Na] 300.1 (PhenomenexLuna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz,CDCl₃) δ ppm 7.12-7.22, m, H, 4.96, s, 2H, 4.92-4.99, m, 1H.

Following Procedure 140, benzyl1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxopropan-2-ylcarbamatewas prepared as yellow solid (13 mg, 25% yield). HPLC: RT=4.15 min [M+H]685.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.26-7.51, m, 6H, 7.18-7.23, m, 1H,6.97-7.15, m, 7H, 6.84-6.93, m, 3H, 6.58-6.61, m, 2H, 5.71-5.98, t,J=34, 1H, 5.73, m, 1H, 5.07-5.11, m, 2H, 4.87, m, 1H, 3.81 3.90, m, 1H,3.69 3.73, m, 1H.

To a solution of benzyl1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxopropan-2-ylcarbamate(10 mg, 0.014 mmol) in CH₂Cl₂ (0.5 m) was added TMSI (18 mg, 0.094mmol). The reaction mixture was sealed and stirred at rt for 20 h. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by prep HPLC (Phenomenex Luna AXIA 5μ 21.2×100 mm, 10%-90%ACN/H₂O containing 0.1% TFA, flow rate 20 mL/min, gradient time 10 min)to yield2-amino-3,3,3-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)propanamide(Example 324) as a white solid (5 mg, 65% yield). HPLC: RT=1.90 min[M+H] 551.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82-7.85, m, 1H, 7.19-7.23, m, 1H,7.11-7.17, m, 2H, 7.07-7.11, m, 1H, 6.98-7.03, m, 3H, 6.89-6.93, m, 2H,6.80-6.86, m, 1H, 6.61-6.64, m, 2H, 5.73-5.99, t, J=52, 1H, 4.00-4.03,J=12, d, 1H, 3.98, m, 1H, 3.63-3.67, d, J=12, 1H;

Example 325

3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideProcedure 143

A solution of 3-amino-4,4,4-trifluorobutanoic acid (628 mg, 4 mmol) andisobenzofuran-1,3-dione (592 mg, 4 mmol) in DMF (5 mL) was heated to140° C. under microwave irradiation for 15 min. The reaction mixture waspurified by preparative HPLC (Axia luna column, 30×75 mm, 10-100%ACN/H₂O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at220 nm) to yield 3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluorobutanamide(620 mg, 54% yield). LCMS: RT=1.54 min [M+H] 288.2 (Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing0.1% TFA; 5 mL/min, monitoring at 220 nm).

3-(1,3-Dioxoisoindolin-2-yl)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 325) was prepared as white solid (12 mg, 27% yield) asdescribed in Procedure 140. LCMS: RT=3.62 min [M+H] 695.3 (PhenomenexLuna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.76-7.88 (4H, m), 7.15-7.01 (3H, m), 6.91-6.97 (2H, m),6.80-6.86 (2H, m), 6.61-6.72 (3H, m), 6.54 (2H, dd, J=13.26, 7.71 Hz),6.21 (1H, d, J=4.55 Hz), 5.84 (1H, t, J=2.78 Hz), 5.25 (1H, m), 3.87(1H, d, J=13.14 Hz), 3.71 (1H, ddd, J=15.66, 11.49, 4.42 Hz), 3.62-3.55(1H, m), 2.85-2.95 (1H, m).

Example 326

3-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideProcedure 144

To a solution of3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 325, 30 mg, 0.04 mmol) in MeOH (1 mL) was added hydrazine (0.03mL, 1 mmol) and the reaction mixture was heated at 50° C. for 4 h. Thereaction mixture was purified by preparative HPLC (Axia luna column,30×75 mm, 10-100% ACN/H₂O with 0.1% TFA over 10 min, flow rate 40mL/min, monitoring at 220 nm) to yield3-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 326) as white solid (7 mg, 24% yield). LCMS: RT=3.62 min [M+H]565.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.34 (1H, d, J=17.94 Hz), 7.13-7.24(3H, m), 6.96-7.11 (4H, m), 6.82-6.92 (3H, m), 6.62 (2H, d, J=7.83 Hz),5.86 (1H, t, J=1.77 Hz), 3.88 (1H, t, J=12.63 Hz), 3.75-3.84 (1H, m),3.70 (1H, d, J=13.14 Hz), 2.82-2.93 (1H, m), 2.77 (1H, m).

Example 327

3-amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-olProcedure 145

To a solution of2-amino-4,4,4-trifluoro-N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide,prepared as described in Example 293, (20 mg, 0.028 mmol) in THF (0.5mL) was added borane (0.2 mL, 1.0 M solution in THF). After hydrogenevolution ceased, the solution was heated in a sealed microwave vialunder microwave irradiation at 100° C. for 5 min. The solvents wereremoved under a stream of nitrogen then THF (0.5 mL) was added to theresidue followed by BF₃.Et₂O (30 mg, 0.21 mmol) and LAH (0.2 mL, 1.0 Msolution in THF). After evolution of hydrogen gas had ceased, the sealedmicrowave vial was heated at 100° C. for 10 min. The solvents wereremoved under a stream of nitrogen and the residue dissolved in NH₄OH(ca. 10 mL). LiCl (10%, ca. 10 mL) was added and the aqueous extractedwith DCM (3×10 mL). The combined organic portions were concentratedunder reduced pressure and purified by preparative TLC (25×25 mm, silicagel 1 mm elution with hexane:EtOAc 4:1).3-Amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-ol(Example 327, 5 mg, 20% yield) was isolated as a colorless oil at R_(f)of 0.5. LCMS: RT=3.88 min [M+H] 693.1 (Phenomenex Luna C18 column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1%TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.88 min, Purity 91%(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400MHz ¹H (CDCl₃) 7.15 ppm, 3H, m; 7.05 ppm, 1H, m; 6.86 ppm, 2H, d, J=8.0Hz; 6.83 ppm, 3H, m; 6.61 ppm, 2H, d, J=8.0 Hz; 5.87 ppm, 1H, t,t,J=52.0 Hz and J=4.0 Hz; 4.41 ppm, 1H, sept, J=8.0 Hz; 3.57 ppm, 1H, d,J=12.0 Hz; 3.48 ppm, 1H, d, J=12.0 Hz; 2.99 ppm, 2H, m; 2.53 ppm, 1H,brt; 1.27 ppm, 3H, d, J=8.0 Hz; 1.25 ppm, 3H, d, J=8.0 Hz.

Example 328

(R)-1-(3,3-difluorocyclobutyl)-3-(1-(3-((dimethylamino)methyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureaProcedure 146

Following Procedure 3, 62, 5 and 6,N-(1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared and the diastereomer mixture was separated by chiralpreparative HPLC (Chiralpak AD column, 5×50 cm isocratic elution with60% IPA/heptane, 50 mL/min, monitoring at 254 nm) to yield(R)-N-((S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white foam (3.92 g, 33% yield) with a retention time of 40 min.

To a suspension of Pd(OAc)₂ (9 mg, 0.04 mmol) and PPh₃ (2 mg, 0.008mmol) in DMF was added Bu₄NBr (265 mg, 0.8 mmol),(R)-N-((S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide,prepared as described in Procedure 62, (500 mg, 0.8 mmol), styrene (137mg, 1.3 mmol) and K₂CO₃ (136 mg, 1.0 mmol). The reaction mixture wasdegassed and backfilled with argon several times. The reaction mixturewas heated at 85° C. for 16 h. The reaction mixture was then poured intosat. NH₄Cl and the aqueous phase was extracted with EtOAc. The combinedorganic portions were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by ISCO chromatography (12 gcolumn, 0-30% EtOAc/hexane) to yield(R)-N-((R)-1-(4-fluoro-3-styrylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(119 mg, 23% yield). LCMS: RT=4.62 min [M+H] 632 (Phenomenex Luna C18,50×4.6 mm, 10%-90% H₂O/ACN with 0.1% TFA, 4 min gradient, flow rate 4mL/min, monitoring at 220 nm).

Using the methods described in Procedure 6 and 12,(R,E)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-styrylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureawas prepared as a clear oil (170 mg, 57% yield). LCMS: RT=4.19 min [M+H]661 (Phenomenex Luna C18, 50×4.6 mm, 10%-90% H₂O/ACN with 0.1% TFA, 4min gradient, flow rate 4 mL/min, monitoring at 220 nm).

Procedure 147

To a solution of(R,E)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-styrylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea(509 mg, 0.8 mmol) in DCM (10 ml) at 0° C. was added 4-methylmorpholineN-oxide (104 mg, 0.8 mmol). Ozone was bubbled through the resultingyellow solution for 10 min. The reaction solvent was removed and theresidue was purified by ISCO chromatography (12 g column, 0-30%EtOAc/hexane) to yield(R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureaas a colorless oil (106 mg, 23% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm10.22 (s, 1H), 8.06 (m, 1H), 7.67 (dd, J=6.19, 2.65 Hz, 1H), 7.16 (m,4H), 6.85 (m, 3H), 6.69 (m, 3H), 5.85 (m, 1H), 5.40 (d, J=6.57 Hz, 1H),4.00 (m, 1H), 2.90 (m, 2H).

Procedure 148

To a solution of(R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea(20 mg, 0.03 mmol) in MeOH (2 mL) was added NHMe₂ (0.009 mL) and a dropof acetic acid. The reaction mixture was stirred at rt for 30 min,followed by addition of NaCNBH₃ (2 mg, 0.03 mmol). The reaction mixturewas stirred at rt for 1 h. The solvent was removed under reducedpressure and the residue was partitioned between sat. NaHCO₃ and EtOAc.The organic phase was concentrated and purified by prep HPLC (PhemomenexLuna 5u C18 Axia column, 21×100 mm, 10%-90% H₂O/ACN with 0.1% TFA/,monitoring at 220 nm) to yield(R)-1-(3,3-difluorocyclobutyl)-3-(1-(3-((dimethylamino)methyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea(Example 328, 8 mg, 44% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.28 (d,J=2.27 Hz, 1H), 7.09 (m, 7H), 6.88 (d, J=8.84 Hz, 1H), 6.63 (d, J=7.07Hz, 2H), 6.51 (br. s., 1H), 5.88 (m, 1H), 4.34 (d, J=12.63 Hz, 1H), 4.10(m, 2H), 3.87 (m, 1H), 3.31 (d, J=12.63 Hz, 2H), 2.92 (m, 3H), 2.74 (d,J=2.78 Hz, 3H), 2.70 (d, J=3.28 Hz, 3H), 2.46 (m, 2H).

Example 329A

(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamideExample 329B

(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamideProcedure 149

To a solution of(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone, preparedas described in Procedure 4, (860 mg, 3.0 mmol) in pyridine (6 mL) wasadded hydroxylamine hydrochloride (830 mg, 12.0 mmol) and the reactionmixture was heated at 100° C. for 2 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inEtOAc (50 mL), washed with 1 N HCl (2×20 mL), water (20 mL) and sat.NaCl (20 mL), then dried over MgSO₄, filtered and concentrated underreduced pressure to yield(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime (912mg, 100% yield) as a white solid. TLC (30% EtOAc/hexane) shows twospots, the cis and trans isomers of(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime,that were not separated. LCMS: RT=1.59 min [M+H] 302.1 (2 min PhenomenexLuna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H₂O over 2minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

Procedure 150

To a suspension of(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime (904mg, 3.0 mmol) in EtOH (3 mL) and conc. NH₄OH (15 mL) was added ammoniumacetate (120 mg, 1.6 mmol) followed by zinc powder (1.05 g, 16.2 mmol)and the reaction mixture was heated at reflux for 2 h. The reactionmixture was allowed to cool to rt then filtered. The filtered solid waswashed with 10 N NaOH (15 mL) and EtOAc (15 mL). The combined filtratewas extracted with EtOAc (2×30 mL). The combined organic fractions werewashed with sat. NaCl (2×10 mL) then dried over MgSO₄, filtered andconcentrated under reduced pressure to yield(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (804 mg,93% yield) as a clear, colorless oil. LCMS: RT=0.96 min [M−NH₂] 271.0 (2min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%acetonitrile/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 1.68 (bs, 2H), 5.25(s, 1H), 7.03 (t, J=8.57 Hz, 2H), 7.19 (d, J=7.91 Hz, 1H), 7.29-7.35 (m,3H), 7.48 (s, 1H).

Procedure 151

To a solution of(3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg,1.1 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added acetic formic anhydride(314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride andformic acid at 60° C. for 2 h). The reaction mixture was allowed to warmto room temperature and stirred for 0.5 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified on a 40g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to giveN-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide(327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H]316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%acetonitrile/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 6.13 (bs, 1H), 6.34(d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H).To a solution ofN-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide(327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et₃N (0.79 mL, 5.7mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). Thereaction mixture was allowed to warm to room temperature and stirred for16 h. The reaction mixture was diluted with ice-water (25 mL) andextracted with Et₂O (3×20 mL). The combined organic layers were washedwith sat. NaCl (20 mL), dried over anhydrous Na₂SO₄, the filteredthrough basic alumina. The filtrate was concentrated to give1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene(268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M−NC] 271.0(2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%acetonitrile/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm); IR ν_(max) cm⁻¹ neat: 2139 (N═C); NMR: 500 MHz ¹H(CDCl₃) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H),7.30-7.35 (m, 3H), 7.41 (s, 1H).

Procedure 152

To a solution of1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene(234 mg, 0.79 mmol) in toluene (8 mL) was added tetrabutylammoniumbromide (75 mg, 0.23 mmol) and benzyl bromide (0.185 mL, 1.56 mmol)followed by 50% KOH(aq) (2.5 mL). The reaction mixture was vigorouslystirred for 3 minutes. The reaction mixture was transferred to aseparatory funnel and washed with H₂O (2.5 mL). The organic fraction wasdried over Na₂SO₄, filtered through a pad of basic alumina andconcentrated under reduced pressure. The residue was purified by chiralprep HPLC (Chiralcel OD-H column, 20×250 mm isocratic elution withisopropyl alcohol (10%) and heptane, 20 mL/min, monitoring at 254 nm) togive(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(RT=6.2 minutes, 128 mg, 42% yield) and(S)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(RT=7.8 minutes, 128 mg, 42% yield) as clear colorless oils. LCMS:RT=1.94 min [M−NC] 361.1 (2 min Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% acetonitrile/H₂O over 2 minutes containing 0.1% TFA;5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 3.61 (d,J=13.18 Hz, 1H), 3.67 (d, J=13.18 Hz, 1H), 6.83 (d, J=7.47 Hz, 2H), 7.08(t, J=8.57 Hz, 2H), 7.17-7.34 (m, 8H).

The reaction could be run in 16% ee of the (R) isomer by substitutingN-benzylcinchoninium chloride in place of tetrabutylammonium bromide andrunning the reaction at 0° C. for 1 h.

Procedure 153

To a solution of1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(20 mg, 0.052 mmol) in MeOH (0.4 mL) was added 4 N HCl in dioxane (0.3mL) and the reaction mixture was stirred for 3 minutes. The reactionsolvent was evaporated under a stream of nitrogen. The residue wasdiluted with 1 N NaOH (5 mL) and the aqueous portion was extracted withEt₂O (3×5 mL). The combined organic fractions were washed with sat. NaCl(5 mL), dried over Na₂SO₄, filtered and evaporated under vacuum to yield1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine(19 mg, 97% yield) as a clear glass.

Procedure 154

To a solution of(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(22 mg, 0.057 mmol) in CH₂Cl₂ (0.10 mL) was added3,3,3-trifluoropropanal (0.010 mL, 0.11 mmol) and pyridine (0.018 mL,0.23 mmol) followed by trifluoroacetic acid (0.009 mL, 0.11 mmol). Thereaction mixture was heated at 40° C. for 4 h. Additional3,3,3-trifluoropropanal (0.010 mL, 0.11 mmol) was added and heating at40° C. for was continued for 2 h. The reaction mixture was allowed tocool to room temperature and the solvent was removed under a stream ofnitrogen. The residue was purified by prep TLC plate, eluting with 40%Et₂O/hexane, to yield(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329A, 11 mg, 36% yield) and(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329B, 11 mg, 36% yield) as clear colorless oils.(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329A): LCMS: RT=1.81 min [M+H] 518.2 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% acetonitrile/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H(CDCl₃) δ ppm 2.24-2.36 (m, 1H) 2.81-2.91 (m, 2H), 3.74 (d, J=13.18 Hz,1H), 3.99 (d, J=13.18 Hz, 1H), 4.43 (dd, J=10.11, 3.52 Hz, 1H), 6.60 (d,J=7.47 Hz, 2H), 6.99-7.07 (m, 4H), 7.12-7.28 (m, 6H), 7.70 (s, 1H).(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329B): LCMS: RT=1.82 min [M+H] 518.2 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% acetonitrile/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H(CDCl₃) δ ppm 2.23-2.35 (m, 1H), 2.77-2.88 (m, 2H), 3.73 (d, J=12.75 Hz,1H), 3.99 (d, J=12.74 Hz, 1H), 4.45 (dd, J=8.35, 3.95 Hz, 1H), 6.61 (d,J=7.47 Hz, 2H), 6.98-7.04 (m, 4H), 7.16-7.28 (m, 6H), 7.69 (s, 1H). Thestereochemistry of(S)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329A) and(R)-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 329B) was assigned arbitrarily.

Example 330

N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxybutanamideProcedure 155

To a solution of(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide(Example 251, 51 mg, 0.1 mmol), in MeOH (1 mL) was added NaBH₄ (10 mL,0.26 mmol). The reaction mixture was stirred at rt for 1 h andconcentrated under reduced pressure. The residue was purified bypreparative HPLC (Axia luna column, 30×100 mm, 40-100% MeOH/H₂O with0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) toyieldN-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxybutanamide(Example 330) as a pale yellow oil (28 mg, 55% yield). LCMS: RT=2.66 min[M+H] 512.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.13-7.23 (3H, m), 7.02-7.08 (2H, m,J=4.96, 4.56, 4.56, 2.43, 2.43 Hz), 6.96-7.02 (2H, m), 6.85-6.93 (4H,m), 6.67 (2H, d, J=7.07 Hz), 5.87 (1H, t, J=2.78 Hz), 4.10-4.20 (1H, m),3.95 (1H, dd, J=12.76, 10.74 Hz), 3.73 (1H, dd, J=12.76, 10.74 Hz),2.32-2.38 (2H, m), 1.22 (3H, d, J=6.32 Hz).

Example 331

(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(hydroxyimino)-3-oxobutanamideProcedure 156

To a solution of(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide(Example 251, 62 mg, 0.12 mmol), in acetic acid (0.5 mL) was addeddropwise a solution of NaNO₂ (25 mg, 0.36 mmol) in H₂O (0.5 mL). Thereaction mixture was stirred at rt for 10 min and diluted with H₂O (10mL). The aqueous portion was extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure to yield(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(hydroxyimino)-3-oxobutanamide(Example 331) as a yellow solid (65 mg, 100% yield). LCMS: RT=1.99 min[M+H] 539.4 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). ¹H NMR (400 MHz, CDCl₃) δ ppm 10.07 (1H, s), 7.15-7.21 (2H, m),7.07-7.14 (7H, m), 7.00-7.05 (4H, m), 6.84-6.96 (6H, m), 6.55-6.60 (2H,m), 5.88 (1H, t, J=2.78 Hz), 3.91 (1H, d, J=13.14 Hz), 3.72-3.80 (1H,m), 2.52 (3H, s).

Example 332A

(S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamideExample 332B

(R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamideProcedure 157

To a solution of(S)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzeneprepared as described in Procedure 149, 150, 151 and 152 (23 mg, 0.060mmol) in THF (0.25 mL) was added 3,3,3-trifluoropropanal (0.006 mL,0.071 mmol) and acetic acid (0.004 mL, 0.071 mmol) followed by a 0.5Msolution of zinc chloride in THF (0.142 mL, 0.071 mmol). The reactionmixture was heated at 55° C. for 16 h. The reaction mixture was allowedto cool to room temperature then a solution of 25% NaOMe in MeOH (25 uL)was added and the reaction mixture was heated at 40° C. for 18 h. Thereaction mixture was allowed to cool to room temperature then a drop ofacetic acid was added and the solvent was removed under a stream ofnitrogen. The residue was purified by prep TLC plate, eluting with 25%EtOAc/hexanes, to yield(S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332A, 7 mg, 22% yield) and(R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332B, 6 mg, 18% yield) as clear colorless oils.(S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332A): LCMS: RT=1.82 min [M+H] 518.2 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% acetonitrile/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H(CDCl₃) δ ppm 2.23-2.35 (m, 1H) 2.77-2.88 (m, 2H) 3.73 (d, J=12.75 Hz,1H) 3.99 (d, J=12.74 Hz, 1H) 4.45 (dd, J=8.57, 4.17 Hz, 1H) 6.61 (d,J=7.47 Hz, 2H) 6.98-7.04 (m, 4H) 7.16-7.28 (m, 6H) 7.69 (s, 1H).(R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332B): LCMS: RT=1.81 min [M+H] 518.2 (2 min Phenomenex Luna C18column, 4.6×30 mm eluting with 10-90% acetonitrile/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H(CDCl₃) δ ppm 2.23-2.34 (m, 1H) 2.77-2.88 (m, 2H) 3.73 (d, J=12.75 Hz,1H) 3.99 (d, J=12.74 Hz, 1H) 4.44-4.47 (m, 1H) 6.61 (d, J=7.47 Hz, 2H)6.98-7.07 (m, 4H) 7.14-7.28 (m, 6H) 7.69 (s, 1H). The stereochemistry of(S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332A) and(R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide(Example 332B) was assigned arbitrarily.

Example 333

1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((R)-2-oxocyclopentyl)ureaExample 334

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-oxocyclopent-1-enyl)ureaProcedure 158

To a solution of oxalyl chloride (2 M in CH₂Cl₂, 150 uL) at −78° C. wasadded DMSO (47 mg, 0.60 mmol) dropwise. The reaction mixture was stirredat −78° C. for 15 min, then1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)urea(Example 246, 113 mg, 0.20 mmol) in CH₂Cl₂ (1 mL) was added dropwise.The reaction mixture was allowed to warm to rt and stirred for 16 h. Thereaction mixture was concentrated under reduced pressure and purified byISCO flash chromatography with EtOAc and hexane as eluting solvent toyield(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-oxocyclopent-1-enyl)urea(Example 333) as a white solid (15 mg, 14% yield) and1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((R)-2-oxocyclopentyl)urea(Example 334) as a white solid (66 mg, 60% yield).(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-oxocyclopent-1-enyl)urea:HPLC: RT=3.99 min [M+H] 551.09 (Phenomenex Luna C18 column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.24-1.37(m, 1H), 1.36-1.58 (m, 1H), 1.68-1.84 (m, 1H), 1.84-2.00 (m, 2H),2.12-2.30 (m, 3H), 2.48-2.73 (m, 1H), 3.58-4.05 (m, 3H), 5.35-5.52 (m,1H), 5.64-6.03 (m, 2H), 6.62-6.78 (m, 2H), 6.78-7.02 (m, 5H), 7.04-7.23(m, 5H).1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((R)-2-oxocyclopentyl)urea:HPLC: RT=4.09 min [M+H] 549.1 (Phenomenex Luna C18 column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.84-1.94(m, 2H), 2.43-2.62 (m, 2H) 3.92 (dd, 2H) 5.82 (t, 1H) 6.62-6.78 (m, 2H)6.79-6.88 (m, 1H) 6.90-7.01 (m, 5H), 7.01-7.15 (m, 3H), 7.14-7.25 (m,2H), 7.62-7.74 (m, 1H), 8.09-8.25 (m, 1H).

Example 335

(R)-3,3,3-trifluoro-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dihydroxypropanamideProcedure 159

To a solution of(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(26 mg, 0.067 mmol) prepared as described in Procedure 4, 149, 150, 151and 152, in CH₂Cl₂ (0.7 mL) at −78° C. was added trifluoroaceticanhydride (0.06 mL, 0.42 mmol) and the reaction mixture was allowed towarm to −40° C. over 6 h. The reaction mixture was quenched by theaddition of H₂O (5 mL) then allowed to warm to room temperature. Themixture was extracted with CH₂Cl₂ (3×5 mL) then dried over Na₂SO₄,filtered and volatiles removed under vacuum. The residue was purifiedusing silica gel (4 g), eluting with 0 to 100% Et₂O/hexane, to give(R)-3,3,3-trifluoro-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dihydroxypropanamide(Example 335, 11 mg, 32%) as a clear colorless glass. LCMS: RT=1.69 min[M−H] 518.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% acetonitrile/H₂O over 2 minutes containing 0.1% NH₄Ac; 5 mL/min,monitoring at 220 nm); NMR: 400 MHz ¹H (CDCl₃) δ ppm 3.71 (d, J=13.18Hz, 1H) 3.92 (d, J=13.18 Hz, 1H) 6.61 (d, J=7.47 Hz, 2H) 6.98-7.06 (m,4H) 7.12-7.30 (m, 7H).

Example 336

2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideProcedure 160

To a solution of(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene(35 mg, 0.09 mmol) prepared as described in Procedure 4, 149, 150, 151and 152, in THF (0.7 mL) was added 3,3,3-trifluoropropanal (0.008 mL,0.095 mmol), 2, 3,4,6-O-pivaloyl-β-D-galactopyranosylamine (49 mg, 0.095mmol) and formic acid (0.004 mL, 0.10 mmol). The reaction mixture wascooled to −20° C. then a 0.5 M solution of zinc chloride in THF (0.19mL, 0.095 mmol) was added and the reaction mixture was stirred at 0° C.for 16 h. Additional 3,3,3-trifluoropropanal (0.016 mL, 0.19 mmol), 2,3,4,6-O-pivaloyl-β-D-galactopyranosylamine (98 mg, 0.19 mmol), formicacid (0.008 mL, 0.20 mmol) and zinc chloride solution (0.38 mL, 0.19mmol) were added and the reaction mixture was allowed to warm to roomtemperature and stirred for 3 h. The volatiles were removed under vacuumand the residue was dissolved in CH₂Cl₂ (5 mL) and washed with sat.NaHCO₃ (2×10 mL) and H₂O (10 mL) then dried over MgSO₄, filtered andvolatiles removed under vacuum. The flask containing the residue wascooled in an ice bath then sat. HCl in methanol (2 mL) was added and thereaction mixture was stirred for 0.5 h at 0° C. then rt for 1.5 h. H₂O(0.5 mL) and MeOH (1.5 mL) were added and the reaction mixture wasstirred for 24 h. Most of MeOH was removed under a stream of nitrogenthen the reaction mixture was diluted with 1 N NaOH (5 mL) and extractedwith CH₂Cl₂ (3×5 mL). The combined organic fractions were washed withH₂O (5 mL), dried over Na₂SO₄, filtered and volatiles removed undervacuum. The residue was purified by prep HPLC (RT=6.2 min using AxiaLuna 5μ C18 30×100 mm column with flow rate of 40 mL/min over minperiod. 20 to 100% solvent B. Solvent A=10/90/0.1% ACN/H₂O/TFA. SolventB=90/10/0.1%) to give the trifluoroacetic acid salt of2-amino-4,4,4-trifluoro-N-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 336, 9 mg, 15% yield) as a clear colorless glass. LCMS: RT=1.34min [M+H] 517.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm elutingwith 10-90% acetonitrile/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm); NMR: 400 MHz ¹H (CD₃Cl) δ ppm 2.59-2.70(m, 1H), 2.72-2.84 (m, 1H), 3.93-4.03 (m, 2H), 4.34 (dd, J=9.01, 3.73Hz, 1H), 6.68-6.72 (m, 2H), 7.02-7.09 (m, 2H), 7.11-7.22 (m, 3H),7.25-7.40 (m, 5H).

Example 337

2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamideProcedure 161

To a solution of(S)-N-((R)-1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide,prepared as described in Procedure 109, 110, 111, 112, 113, 114, (0.545g, 1 mmol) in CH₂Cl₂ (10 mL) was added Cu(OAc)₂ (0.182 g, 1 mmol),followed by pyridine (0.79 g, 10 mmol) and2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (0.159 g, 0.66 mmol). Thereaction mixture was stirred overnight under ambient air and filteredthrough a plug of celite and neutral alumina. The solid was washed withethyl acetate and the filtrate was concentrated under reduced pressureto yield(S)-N-((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas an off-white foam (0.495 g, 87% yield). LCMS: RT=3.653 min [M+H]572.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueousacetonitrile containing 0.1% trifluoroacetic acid over a 4 minutegradient, monitoring at 220 nM). ¹H NMR (CDCl₃) ppm 7.2-7.1 (m, 5H),7.02 (d, J=6.2 Hz, 1H), 6.89 (d, J=6.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H),6.68 (br, 2H), 6.54 (dd, J=6.2 Hz, 13.6 Hz, 1H), 5.84 (t, J=52.7 Hz,1H), 4.62 (dd, J=2.2 Hz, 13.6 Hz, 1H), 4.40 (dd, J=2.2 Hz, 5.7 Hz, 1H),4.21 (s, 1H), 3.95 (d, J=12.8 Hz, 1H), 3.55 (d, J=12.7 Hz, 1H), 1.19 (s,9H).

To an oven-dried 3-necked 25 mL RB flask under nitrogen was added CH₂Cl₂(3.5 mL) and 1 M diethylzinc solution in hexane (3.43 mL, 3.43 mmol).The flask was cooled in an ice-bath and a solution of trifluoroaceticacid (0.391 g, 3.43 mmol) in CH₂Cl₂ (1 mL) was added dropwise viasyringe. After stirring for 15 min, a solution of diiodomethane (0.918g, 3.43 mmol) in CH₂Cl₂ (1 mL) was added. The reaction mixture wasstirred at rt for 15 min, followed by addition of(S)-N-((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(0.495 g, 0.87 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was allowedto warm to rt and stirred for 4 h. The reaction mixture was diluted withCH₂Cl₂ and washed successively with sat. sodium bicarbonate, water, sat.NaCl, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by ISCO using a gradient of 5-70%EtOAc/hexane as eluent to yield(S)-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white foam (0.347 g, 71% yield). HPLC: RT=3.668 min [M+H] 586.3(Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous acetonitrilecontaining 0.1% trifluoroacetic acid over a 4 minute gradient,monitoring at 220 nm). ¹H NMR (CDCL₃) ppm 7.2-7.05 (m, 6H), 6.91 (d,J=6.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.71 (m, 2H), 5.84 (t, J=53.1 Hz,1H), 4.21 (s, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.62 (m, 1H), 3.56 (d,J=12.8 Hz, 1H), 1.22 (s, 9H), 0.72-0.65 (m, 4H).

Following Procedure 6, 90, 91 and 92,2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide(Example 337) was prepared. HPLC: RT=3.466 min [M+H] 705.3 (PhenomenexLuna C18 5μ column, eluting with 10-90% aqueous acetonitrile containing0.1% trifluoroacetic acid over a 4 minute gradient, monitoring at 220nM). ¹H NMR (CD₂Cl₂) ppm 8.97 (s, 1H), 7.14-6.5 (m, 11H), 5.84 (t,J=53.1 Hz, 1H), 3.79 (d, J=12.3 Hz, 1H), 3.67 (s, 1H), 3.62 (d, J=13.1Hz, 1H), 3.52 (m, 1H), 1.48 (br, 1H), 0.55 (m, 4H).

Example 338

(R)-N-(1-(3-cyclopentyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 162

To a solution of(S)-N-(1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide,prepared as described in Procedure 3, 62, 5, 6 and 7 in THF (0.1 M, 0.5mL, 0.05 mmol) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (4 mg, 0.0054 mmol) and tricyclohexylphosphine (1.0 M intoluene, 0.05 mL, 0.05 mmol), followed by cyclopentyl zinc bromide (0.5M in THF, 0.04 mL, 0.2 mmol). The reaction mixture was heated at 100° C.under microwave irradiation for 15 min. The reaction mixture was cooledand filtered through a plug of silica. The solid was washed with THF (2mL) and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in methanol (1 mL) and purified by preparativeHPLC (RT=14.89 min, Sunfire Prep C18 OBD 19×100 mm eluting with 18-90%MeCN/H₂O over 12 minutes and at 90% for 8 additional minutes containing0.1% TFA; 20 mL/min, monitoring at 220 nm) to yield(R)-N-(1-(3-cyclopentyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 338) as a colorless gum (13 mg, 19% yield). LCMS: RT=4.56 min[M+H] 684.3 (4 min Sunfire S5 C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). ¹H NMR (500 MHz, CD₃Cl) δ ppm 7.90 (1H, d, J=6.60 Hz), 7.84 (1H,dd, J=8.25, 4.40 Hz), 7.28 (1H, t, J=9.07 Hz), 7.23 (1H, t, J=7.42 Hz),7.16 (2H, t, J=7.42 Hz), 7.01-7.05 (2H, m), 6.92-6.96 (2H, m), 6.86 (1H,dd, J=6.60, 2.75 Hz), 6.79-6.82 (1H, m), 6.69 (2H, d, J=7.15 Hz), 6.65(1H, s), 5.75-5.98 (1H, t), 4.12 (1H, d, J=13.20 Hz), 3.66 (1H, d,J=13.20 Hz), 3.14-3.21 (1H, min), 1.94-2.03 (2H, m), 1.62-1.72 (4H, m),1.43-1.48 (1H, m), 1.36-1.42 (1H, m).

Example 339

(R)-methyl2-(2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenoxy)-2-methylpropanoateProcedure 163

A solution of(R)-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamidebenzamide, prepared as described in Example 264, (226 mg, 0.4 mmol),methyl 2-bromo-2-methylpropanoate (0.10 mL) and K₂CO₃ (326 mg, 2.36mmol) in DMF (1 mL) was heated at 180° C. under microwave condition for1200 seconds. The reaction mixture was allowed to cool, diluted withEtOAc and the organic layer was washed with H₂O (2×), saturated NaCl,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby ISCO flash chromatography (silica gel, hexanes/EtOAc) to give(R)-methyl2-(2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenoxy)-2-methylpropanoate(Example 273, 76 mg, yield: 29%). LCMS: RT=2.26 min [M+H] 666.4(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

Example 340

(R)-N-(1-(3-(benzylamino)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 164

To a solution of(3-bromo-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)methanone,prepared as described in Procedure 62, (110 mg, 0.27 mol) in DMSO (2 mL)at rt was added benzylamine (43 μL, 0.4 mol), copper (I) iodide (5 mg,0.03 mol), L-proline (23 mg, 0.05 mol), and potassium carbonate (55 mg,0.4 mol). The reaction mixture was degassed and heated for 4 h at 70° C.After cooling to rt, the reaction mixture was partitioned between waterand EtOAc. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified via ISCOchromatography (4 g column, 0-30% EtOAc/hexane) to yield(3-(benzylamino)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneaas a clear, colorless oil (95 mg, 81% yield). ¹H NMR (400 MHz, CDCl₃) δppm 7.90 (dd, J=6.57, 2.02 Hz, 1H), 7.79 (m, 1H), 7.27 (m, 10H), 6.95(m, 3H), 6.87 (dd, J=8.59, 2.53 Hz, 1H), 6.73 (d, J=7.07 Hz, 2H), 6.54(m, 2H), 5.87 (m, 1H), 4.40 (s, 2H), 3.75 (d, J=13.14 Hz, 1H).

Using the methods described in Procedures 5, 6 and 7,(R)-N-(1-(3-(benzylamino)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 340) was prepared as a white solid (8 mg, 59% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.90 (dd, J=6.57, 2.02 Hz, 1H), 7.79 (m, 1H),7.27 (m, 10H), 6.95 (m, 3H), 6.87 (dd, J=8.59, 2.53 Hz, 1H), 6.73 (d,J=7.07 Hz, 2H), 6.54 (m, 2H), 5.87 (m, 1H), 4.40 (s, 2H), 3.75 (d,J=13.14 Hz, 1H).

Example 341

(R,E)-methyl3-(2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)phenyl)acrylateProcedure 165

To a solution of(R)-N-((S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide,prepared as described in Procedure 3, 62, 5 and 6, (500 mg, 0.82 mmol)in DMF (5 mL) at rt was added methyl acrylate (0.74 mL, 8.22 mmol), Pd₂(dba)₃ (75 mg, 0.082 mmol), tri-t-butyl phosphine (89 μL, 0.33 mmol),and cesium carbonate (536 mg, 1.64 mmol). The reaction mixture wasdegassed with argon and was heated at 100° C. for 4 h. The reactionmixture was poured into water and the aqueous phase extracted with ethylacetate. The combined organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by ISCOchromatography (4 g column, 0-40% EtOAc/hexane) to yield (E)-methyl3-(5-((R)-1-((R)-1,1-dimethylethylsulfinamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-fluorophenyl)acrylateas a white foam (485 mg, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77(d, J=16.42 Hz, 1H), 7.59 (dd, J=6.69, 2.15 Hz, 1H), 7.41 (m, 1H), 7.16(m, 4H), 6.94 (dd, J=7.33, 1.77 Hz, 2H), 6.86 (d, J=8.84 Hz, 1H), 6.73(t, J=4.93 Hz, 2H), 6.53 (d, J=16.17 Hz, 1H), 5.88 (m, 1H), 4.29 (s,1H), 4.03 (d, J=12.38 Hz, 1H), 3.79 (s, 3H), 3.62 (d, J=12.38 Hz, 1H),1.24 (m, 9H).

Using the methods described in Procedures 6 and 7, (R,E)-methyl3-(2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)phenyl)acrylate(Example 341) was prepared as a white solid. LCMS: RT=4.46 min [M+H+60]781 (Phemonenex Luna C18, 50×4.6 mm, 4 min gradient, eluting with105-90% MeOH/H₂O containing 0.1% TFA, monitoring at 220 nm). ¹H NMR (400MHz, CDCl₃) δ ppm 7.92 (m, 1H), 7.83 (m, 1H), 7.69 (d, J=16.42 Hz, 1H),7.28 (m, 3H), 7.18 (m, 2H), 7.09 (t, J=9.35 Hz, 1H), 6.94 (m, 3H), 6.72(m, 3H), 6.51 (m, 1H), 6.42 (d, J=16.42 Hz, 1H), 6.42 (d, J=16.42 Hz,1H),), 5.88 (m, 1H), 3.95 (d, J=14.91 Hz, 1H), 3.82 (m, 4H).

Example 342

3-amino-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamideProcedure 166

To a solution of(R)-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutamide(Example 251, 27 mg, 0.053 mmol) in CH₃CN (1 mL) was added Cbz-NH₂ (24mg, 0.16 mmol), followed by triethylsilane (0.5 mL, 3 mmol), and TFA(0.4 mL, 5.3 mmol). The reaction mixture was stirred at rt for 3 days.The reaction mixture was concentrated and the residue was dissolved in amixture of CH₃OH (1 mL) and CHCl₃ (1 mL) and 10 wt % Pd/C (20 mg) wasadded. The reaction mixture was stirred under H₂ for 16 h and the solidwas filtered. The filtrate was concentrated under reduced pressure andthe residue was purified by prep HPLC (Phenomenex Luna Axia, 5u 30×100,eluting with 10%-90% MeOH/H₂O containing 0.1% TFA, gradient time 10 min,flow rate 40 ml/min, monitoring at 220 nm) to yield3-amino-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide(Example 342, 5 mg, 19% yield). HPLC: RT=3.28 min [M+H] 511.3(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); ¹H NMR(400 MHz, CDCl₃) δ ppm 7.15-7.24, m, 3H, 6.97-7.10, m, 4H, 6.83-6.92, m,3H, 6.60-6.64, m, 3H, 5.73-6.60, t, J=54, 3.81-3.91, m, 1H, 3.67-3.76,m, 1H, 3.59, m, 1H, 2.70, m, 2H, 1.31, m, 3H.

Example 343

(R)-1-(tert-Butyldimethylsilyl)-N-((R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-oxoazetidine-2-carboxamideProcedure 167

To a solution of(R)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid (126mg, 0.55 mmol) in THF (1.5 mL) was added to a solution of triphosgene(54 mg, 0.18 mmol). The reaction mixture was stirred for 5 min at rt,followed by addition of 2,4,6-trimethylpyridine (203 μL, 1.54 mmol), asolution of(R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine,prepared as described in Procedure 3, 62, 5 and 6, (50 mg, 0.11 mmol) inTHF (0.6 mL), and N,N-diisopropylethylamine (268 μL, 1.54 mmol). Thereaction mixture was stirred at room temperature for 40 min. Water (10mL) was added and the reaction mixture was extracted withdichloromethane (3×15 mL) and the combined organic layers were washedwith 2 N potassium carbonate and then sat. NaCl. The organic layers weredried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by ISCO Flash chromatography(Analogix column 4.2 g, eluting with hexane/EtOAc) to yield(R)-1-(tert-Butyldimethylsilyl)-N-((R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-oxoazetidine-2-carboxamide(Example 343, 41 mg, 55% yield). LCMS: RT=4.18 min [M+H] 667.1(Phenominex, Luna C18, 4.6×50 mm, 10%-90% MeOH/H₂O containing 0.1% TFA,flow rate 4 mL/min, 4 min gradient, monitoring at 220 nm); ¹H NMR (500MHz, CDCl₃) δ ppm −0.04 (s, 3H), 0.24 (s, 3H), 0.91 (s, 9H), 2.79 (dd,J=15.4, 2.7 Hz, 1H), 3.32 (dd, J=15.4, 6.6 Hz, 1H), 3.79-3.85 (m, 1H),3.86-3.90 (m, 2H), 3.91 (s, 3H), 5.87 (none, 2H), 6.59 (s, 1H), 6.64 (d,J=7.1 Hz, 2H), 6.75 (s, 1H), 6.80 (d, J=9.3 Hz, 1H), 6.87-6.94 (m, 4H),7.15 (t, J=7.4 Hz, 2H), 7.20 (d, J=7.1 Hz, 1H).

Example 344

((R)-4-fluoro-N-(1-(4-fluoro-3-(hydrazinecarbonyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 168

To a solution of(R)-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoicacid, prepared as described in Procedures 3, 62, 5, 6, 7, 56, 57 and 23,(30 mg, 0.045 mmol) in dichloromethane (1 mL) was addedhydroxybenzotriazole (8 mg, 0.058 mmol), followed by EDCI (11 mg, 0.058mmol). The reaction mixture was stirred for 15 min at rt, then hydrazinehydrate was added (3 μL, 0.001 mmol) and the reaction mixture wasstirred for an additional 15 min. The reaction mixture was loaded on anISCO cartridge (4 g column) and eluted with 0 to 100% EtOAc in hexane toyield(R)-4-fluoro-N-(1-(4-fluoro-3-(hydrazinecarbonyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 344, 25 mg, 81% yield) as a white solid. LCMS: RT=1.78 min[M+H] 674 (Chromolith Performance RP-18e column, 4.6×100 mm eluting with10-90% ACN/H₂O over 2 minutes containing 0.1% TFA, 5 mL/min, monitoringat 220 nm).

Example 345

(R)-4-fluoro-N-(1-(4-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideProcedure 169

A solution of(R)-4-fluoro-N-(1-(4-fluoro-3-(hydrazinecarbonyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 344, 35 mg, 0.052 mmol) in trimethyl orthoformate (1 mL) washeated at 100° C. for 16 h. The reaction mixture was concentrated underreduced pressure and the residue was purified by ISCO chromatography (4g column, eluting with 0 to 100% EtOAc in hexane) to yield(R)-4-fluoro-N-(1-(4-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 345, 16 mg, 45% yield) as a white solid. LCMS RT=2.06 min [M+H]698 (Chromolith Performance RP-18e column, 4.6×100 mm eluting with10-90% ACN/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm).

Example 346

(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-formylphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)ureaProcedure 170

To a solution of(R)-1-(1-(4-cyanophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea,prepared as described in Procedure 3, 4, 5, 6, 25 and 56, (59 mg, 0.11mmol) in methanol (2 mL) was added cobalt chloride hexahydrate (50 mg,0.22 mmol), followed by sodium borohydride (40 mg, 1.1 mmol). Thereaction mixture was stirred for 21 h at room temperature then quenchedby addition of hydrochloric acid (1.0 M, 2 mL). The reaction mixture wasextracted with ethyl acetate and the combined organic extracts weredried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by ISCO flash chromatography (12 gsilica gel, 0-100% ethyl acetate/hexane gradient over 11 min., flow rate30 mL/min), then further purified by preparative HPLC (Phenomenex OnyxMonolithic 10×100 mm column; 10-90% acetonitrile/water with 0.1%trifluoroacetic acid gradient over 5 min., 25 mL/min) to yield(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-formylphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea(Example 346) as a white solid (2 mg, 3% yield). LCMS: RT=1.07 min [M+H]561 (Chromolith Performance 18e 4.6×100 mm column, 50-90% methanol/waterwith 0.1% trifluoroacetic acid gradient over 2 min, 5 mL/min); ¹H NMR(400 MHz, CDCl₃) δ ppm 10.00 (1H, s), 7.84 (2H, d, J=8.24 Hz), 7.41 (2H,d, J=8.79 Hz), 7.1-7.20 (5H, m), 6.90 (3H, m), 6.70 (2H, d, J=7.15 Hz),5.88 (1H, tt, J_(HH)=2.75 Hz, J_(HF)=5³ Hz), 5.16 (1H, s), 4.88 (1H, t,J=6.32 Hz), 3.79 (2H, ddd, J=15.67, 9.07, 8.79 Hz).

Example 347

(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamideProcedure 171

To a solution of(R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine,prepared as described in Procedure 109, 110, 111, 112, 113, 114, 161,(24 mg, 0.05 mmol) in CH₂Cl₂ (0.5 mL) was added2-methyl-5(trifluoromethyl)-oxazole-4-carboxylic acid (12 mg, 0.06mmol), followed by PyBrOP (28 mg, 0.06 mmol) and iPr₂NEt (9 mg, 0.065mmol). The reaction mixture was stirred at rt for 72 h. The reactionmixture was concentrated under reduced pressure and the residue waspurified by prep HPLC (Phenomenex Luna 5μ, 30×100 mm, eluting with10%-90% MeOH/H₂O containing 0.1% TFA, gradient time 10 min, flow rate 40mL/min) to yield(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide(Example 347) as a white solid (23 mg, 70% yield). HPLC: RT=2.18 min[M+H] 659.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79, s, 1H, 7.10-7.20, m, 3H,6.90-7.03, m, 5H, 6.70, s, 1H, 6.68, s, 1H, 6.55-6.58, m, 1H, 5.74-6.00,t, J=52; 4.15, 4.19, d, J=16, 1H, 3.66-3.69, d, J=12, 1H, 3.51-3.54, m,1H, 0.73-0.80, m, 1H, 0.61-0.69, m, 2H, 0.55-0.60, m, 1H.

Example 348

(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamideProcedure 172

To a solution of(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone,prepared as described in Procedure 3, 4, 59 and 68, (207 mg, 0.53 mmol)in pyridine (1.5 mL) was added hydroxylamine hydrochloride (192 mg, 2.8mmol) and the reaction mixture was heated at 100° C. for 2 h. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in EtOAc (50 mL). The organic portion was washed with 1 NHCl (2×20 mL), water (20 mL) and sat. NaCl (20 mL), then dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by ISCO (40 g silica gel column, 0-30% EtOAc/hexane over 30min) to yield(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneoxime (216 mg, 77% yield) as a colorless oil. LCMS: RT=2.13 min [M+H]408.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm).

Procedure 173

To a suspension of(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneoxime (3.5 g, 8.6 mmol) in EtOH (30 mL) and conc. NH₄OH (50 mL) wasadded ammonium acetate (754 mg, 19.8 mmol), followed by zinc powder (3.2g, 49.1 mmol) and the reaction mixture was heated at reflux for 3 h. Thereaction mixture was allowed to cool to rt then filtered through celite.The solid was washed with 1 N NaOH (10 mL) and MeOH (10 mL). Thecombined filtrate was extracted concentrated and the residue waspartitioned between EtOAc and water. The organic layer was separated andwashed with 1 N NaOH (15 mL), sat. NaCl (2×10 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to yield(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine(2.8 g, 83% yield) as a light yellow oil. LCMS: RT=1.76 min [M−NH₂]377.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 6.97-7.09 (4H, m), 6.81-6.89 (2H, m),5.76-6.03 (1H, m), 5.14 (1H, s), 4.52 (1H, ddd, J=11.97, 6.15, 6.04 Hz),1.73 (2H, bs), 1.29-1.36 (6H, m).

Procedure 174

To a solution of(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine(2.8 g, 7.1 mmol) in CH₂Cl₂ (30 mL) at 0° C. was added acetic formicanhydride (2.8 mL, formed by heating a 2:1 v/v ratio of acetic anhydrideand formic acid at 60° C. for 2 h). The reaction mixture was allowed towarm to room temperature and stirred for 0.5 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified by ISCO(120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient) togiveN-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide(2.56 g, 85% yield) as a colorless oil. LCMS: RT=1.99 min [M+H] 422.0(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm). To a solution ofN-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide(225 mg, 0.53 mmol) in THF (2 mL) at 0° C. was added Et₃N (0.4 mL, 2.9mmol) followed by phosphorous oxychloride (74 μL, 0.80 mmol). Thereaction mixture was allowed to warm to room temperature and stirred for4 h. The reaction mixture was diluted with ice water (15 mL) andextracted with Et₂O (3×15 mL). The combined organic layers were washedwith sat. NaCl (20 mL), dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by ISCO (12 g silica gel column,0-50% EtOAc/hexane over 30 min) to yield1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene(143 mg, 67% yield) as a pale yellow oil. LCMS: RT=2.13 min [M−NC] 377(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.07-7.13 (1H, m), 6.91-7.03 (4H, m),6.84-6.86 (1H, m), 5.78-6.04 (1H, m), 5.82 (1H, s), 4.54 (1H, ddd,J=11.97, 6.15, 6.04 Hz), 1.35 (6H, t, J=5.05 Hz).

Procedure 175

To a solution of1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene(81 mg, 0.2 mmol) in toluene (2 mL) was added tetrabutylammonium bromide(19 mg, 0.06 mmol) and benzyl bromide (50 mg, 0.22 mmol), followed by50% KOH(aq) (650 μL). The reaction mixture was vigorously stirred for 3minutes. The reaction mixture was diluted with EtOAc (20 mL). Theorganic layer was separated, washed with sat. NaCl (2 mL), dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by ISCO (12 g silica gel column, 0-40% EtOAc/hexane over 35min) to yield racemic (±)-methyl4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoateas a colorless film (87 mg, 79% yield). LCMS RT=2.24 min [M−NC] 525.1(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2H, d, J=7.47 Hz), 7.08 (1H, t,J=9.67 Hz), 6.93-6.99 (5H, m), 6.87 (2H, d, J=6.59 Hz), 5.76-6.03 (1H,m), 4.40-4.46 (1H, m), 3.90 (3H, s), 3.65 (2H, s), 1.27 (6H, dd,J=17.58, 5.71 Hz).

A solution of (±)-methyl4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate(87 mg) in isopropyl alcohol was subjected to chiral preparative HPLC(Chiralpak AD column, 5×50 cm isocratic elution with 10% IPA/heptane, 50mL/min, monitoring at 254 nm) to yield (R)-methyl4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate(35 mg) (chiral analytical HPLC: RT=8.9 min, chiralpak AD 4.6×250 mmcolumn, isocratic elution with 10% IPA/heptane) and (S)-methyl4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate(38 mg) (chiral analytical HPLC: RT=6.3 min, chiralpak AD 4.6×250 mmcolumn, isocratic elution with 10% IPA/heptane) as clear colorless oils.

Procedure 176

To a solution of (R)-methyl4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate(120 mg, 0.22 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (0.5 mL)and the reaction mixture was stirred for 3 minutes. The reaction solventwas evaporated under a stream of nitrogen. The residue was diluted withEtOAc (15 mL), washed with saturated sodium bicarbonate solution (10 mL)and sat. NaCl, dried over MgSO₄, filtered and evaporated to yield(R)-methyl4-(2-amino-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate(103 mg, 86% yield) as a clear glass. LCMS: RT=1.87 min [M−NH₂] 525.1(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm).

Procedure 177

To a solution of (R)-methyl4-(2-amino-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate(50 mg, 0.09 mmol) in THF (2 mL) was added sodium bicarbonate (30 mg,0.36 mmol). The reaction mixture was stirred at rt overnight. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by ISCO (4 g silica gelcolumn, 0-50% EtOAc/hexane over 30 min) to yield (R)-methyl4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate(53 mg, 79% yield) as a colorless film. LCMS: RT=2.28 min [M+H] 731.9(Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H₂Ocontaining 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220nm); HPLC: RT=4.28 min (Phenomenex Luna C18 4.6×50 mm column, elutingwith 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4 mL/min, wavelength220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.95 (1H, d, J=4.83 Hz),7.81-7.84 (3H, m), 7.28-7.32 (1H, m), 6.94-7.04 (4H, m), 6.77-6.79 (2H,m), 6.53-6.63 (3H, m), 5.77-6.01 (1H, m), 4.30-4.35 (1H, m), 4.25 (1H,d, J=12.74 Hz), 3.89 (3H, s), 3.78 (1H, d, J=12.74 Hz), 1.28 (3H, d,J=6.15 Hz), 1.21 (3H, d, J=6.15 Hz).

To a solution of (R)-methyl4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate(20 mg, 0.027 mmol) in THF (2 mL) at −78° C. was added a solution oflithium triethylborohydride (1.0 M in THF, 0.5 mL, 0.5 mmol). Thereaction mixture was stirred at −78° C. for 1.5 h. The reaction wasquenched by the addition of 1 N NaOH (1 mL) and diluted with EtOAc (15mL). The organic portion was washed with sat. NaCl (2×10 mL), dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (YMC Sunfire 5μ C18 30×100 mmcolumn, eluting with 20-90% MeOH/H₂O containing 0.1% TFA, 10 mingradient, flow rate 40 mL/min, wavelength 220 nm) to yield(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide(Example 348, 13 mg, 78% yield) as a colorless film. LCMS: RT=2.17 min[M+H] 704.1 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90%MeOH/H₂O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min,wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mmcolumn, eluting with 10-90% MeOH/H₂O containing 0.2% PPA, flow rate 4mL/min, wavelength 220 nm); ¹H NMR (400 MHz, CDCl₃) δ ppm 7.91 (1H, d,J=6.59 Hz), 7.85-7.87 (1H, m) 7.26-7.31 (1H, m), 7.16 (2H, d, J=7.91Hz), 6.93-7.05 (4H, m), 6.68-6.73 (3H, m), 6.60-6.66 (2H, m), 5.75-6.01(1H, m), 4.64 (3H, s), 4.35 (1H, m), 4.06 (1H, d, J=13.2 Hz), 3.74 (1H,d, J=13.2 Hz), 1.29 (3H, d, J=6.15 Hz), 1.26 (1H, s), 1.23 (3H, d,J=6.15 Hz).

Example 273 can also be prepared by alternate procedures as set forthbelow.

Procedure 178

To a N₂ flushed, 2 L four necked flask equipped with a mechanicalstirrer, a condenser, a temperature controller and a N₂ inlet, was addedpotassium trimethylsilanolate (225.0 g, 1.75 mol, tech. purify 90%),1-bromo-3,5-difluorobenzene (96.5 g, 0.5 mol) and diglyme (300 mL). Thereaction mixture was heated to 120° C. under N₂ for 5 h. After coolingto rt, the heating mantle was replaced with an ice bath. The reactionmixture was acidified with a 3 N HCl solution (600 mL) while keeping thereaction temperature below 30° C. Tertiary butyl methyl ether (1 L) wasadded and the resulting mixture was stirred below 20° C. for 30 min thentransferred to a 5 L separatory funnel. The organic layer was separatedand washed with water (3×500 mL), sat. NaCl (500 mL), dried over MgSO₄,filtered and concentrated in vacuo to give the crude red solid (145.0g). The crude material was then distillated at 52-55° C./0.1 mm Hg toyield 3-bromo-5-fluorophenol as a slightly yellow oil (88.0 g, 92%yield). ¹H NMR (300 MHz, CDCl₃) δ 5.34 (s, H), 6.47-6.52 (m, 1H),6.77-6.83 (m, 2H).

To a flame dried, 1 L, three necked round bottom flask equipped with atemperature controller, a mechanical stirrer, a condenser and a N₂ inletwas charged 3-bromo-5-fluorophenol (57.3 g, 300 mmol),1,2-dibromo-1,1′,2,2′-tetrafluoroethane (156.0 g, 600 mmol), dry DMSO(300 mL) and Cs₂CO₃ (146.6 g, 450 mmol) under N₂. The reaction mixturewas heated to 50° C. for 5 h. After cooling to rt, water (300 mL) andhexane (300 mL) were added. The resulting mixture was stirred at rt for30 min. The organic phase was separated and the aqueous layer wasextracted with hexane (300 mL). The combined organic extracts werewashed with water (500 mL), sat. NaCl (500 mL), dried over MgSO₄,filtered and concentrated in vacuo to give1-bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene (104.2 g,94% yield) containing 5% of1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.2 g).1-Bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene: ¹H NMR(300 MHz, CDCl₃) δ 6.91-6.94 (m, 1H), 7.18-7.23 (m, 2H).

To a 1 L four necked round bottom flask equipped with a temperaturecontroller, a mechanical stirrer, and a N₂ inlet, was added the crudemixture of1-bromo-3-(2-bromo-1,1,2,2,-tetrafluoro-ethoxy)-5-fluorobenzene (104.0g, 281 mmol) and 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene(5.2 g, 18 mmol), acetic acid (300 mL). The reaction mixture was thenheated to 50° C. Zinc dust (91.9 g, 1.405 mol) was added portion wise.The reaction mixture was stirred at 50° C. for 1 h and allowed to coolto rt. Water (300 mL) and hexane (300 mL) were added. The resultingmixture was stirred at rt for 30 min. The organic phase was separatedand the aqueous layer was extracted with hexane (2×300 mL). The combinedorganic extracts were washed with water (500 mL), sat. NaCl (500 mL),dried over MgSO4, filtered and concentrated in vacuo to yield1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a slightlyyellow liquid (71 g, 87% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 5.87 (tt,J=52.7 and 2.9 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.16-7.18 (m, 2H).1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene may be distilledat 0.6 mm Hg, 47-48° C. (bath 77-100° C.) to a colorless oil.

To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene,prepared as described in Procedure N, (1.00 g, 3.44 mmol) in diethylether in (10 mL) at −72° C. was added 2.5 M n-BuLi (1.37 mL, 3.44 mmol)dropwise. Upon completion of addition, the reaction mixture was stirredfor 15 minutes at −72° C., then 4-fluoro-3-methoxybenzaldehyde (0.53 g,3.44 mmol) was added while the reaction mixture temperature wasmaintained below −52° C. The reaction mixture was stirred for 3 h at−72° C. The reaction mixture was quenched by the addition of 1N HCl andthe aqueous portion was extracted with EtOAc (2×). The combined organiclayers were washed with sat. NaCl, dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified by ISCO using agradient of 0-50% EtOAc/hexane as eluent to yield(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(0.83 g, 66% yield). HPLC: RT=3.85 min (Phenomenex Luna C18 5μ column,eluting with 10-90% aqueous methanol containing 0.1% phosphoric acidover a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); ¹HNMR (CDCl₃): 7.05-6.8 (m, 6H), 5.87 (tt, J=2.8, 52.9 Hz), 5.75 (s, 1H),3.85 (s, 3H).

To a solution of(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol(0.58 g, 1.57 mmol) in CH₂Cl₂ (5 mL) was added activated manganesedioxide (0.80 g, 7.86 mmol). The reaction mixture was stirred overnightat rt. Additional manganese dioxide (0.80 g, 7.86 mmol) was added andthe reaction stirred at rt overnight. The reaction mixture was dilutedwith CH₂Cl₂ and filtered through celite and the solid was washed withCH₂Cl₂. The filtrate was concentrated under reduced pressure to yield(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone(0.56 g, 98% yield). HPLC: RT=4.048 minutes (Phenomenex Luna C18 5μcolumn, eluting with 10-90% aqueous methanol containing 0.1% phosphoricacid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220nm); LCMS: [M+H] 365.2 (Phenomenex Luna C18 5μ column, eluting with10-90% aqueous methanol containing 0.1% TFA over a 2 minute gradient,flow rate 5 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CDCl₃):7.5-7.1 (m, 6H), 5.92 (tt, J=2.2, 53.6 Hz, 1H), 3.93 (s, 3H).

Alternatively,(4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanonemay be prepared by the methods described in Procedure 4 from4-fluoro-3-methoxybenzonitrile in 68% yield.

(R)-N-((4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamidewas prepared by the methods described in Procedures 5 yielding a 3:1diastereomeric mixture of(R)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideand(S)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidein 90% yield. The diastereomers were separated by Chiralcel AD columnchromatography elution with Heptane IPA (68% yield). Analytical data andyield for diastereomers in here. Isomer A: LCMS: [M+H] 560.2, retentiontime=4.08 min (Phenomenex Luna C18 5p column, eluting with 10-90%aqueous methanol containing 0.1% TFA over a 4 minute gradient, flow rate5 mL/min, monitoring at 220 nm); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.23 (s, 9H), 3.63 (d, J=12 Hz, 1H), 3.73 (s, 3H), 3.89 (d, J=12 Hz,1H), 5.94 (tt, J=53, 2.4 Hz, 1H), 6.67-6.74 (m, 2H), 6.96-7.03 (m, 3H),7.36-7.14 (m, 6H) ppm. Chiral HPLC: RT=8.21 min (Chiral AD column4.6×250 mm; 20% Isocratic; Solvent A=Heptane, Solvent B=0.1% DEA inIPA). Isomer B: LCMS: RT=4.022 min [M+H] 560.2 (4 min Phenomenex LunaC18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.20 (s, 9H) 3.56 (d, J=12.09 Hz, 1H) 3.77 (s, 3H) 3.98 (d,J=12.64 Hz, 1H) 4.20 (s, 1H) 5.69-6.00 (m, 1H) 6.67-6.74 (m, 2H)6.80-6.89 (m, 2H) 6.91 (d, J=7.70 Hz, 2H) 7.02-7.08 (m, 1H) 7.10 (s, 1H)7.11-7.20 (m, 3H). Chiral HPLC: RT=10.34 min (Chiral AD column 4.6×250mm; 20% Isocratic; Solvent A=Heptane, Solvent B=0.1% DEA in IPA).

(R)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas converted to(R)-4-fluoro-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideby the methods described in Procedure 6 and Procedure 7.

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenyethyl)-3-(trifluoromethyl)benzamide(2.8 g, 4.43 mmol), prepared as described in Procedure 5, 6 and 7 (44%yield), in CH₂Cl₂ (15 mL) was added BBr₃ (12 m, 12 mmol). The resultingmixture was stirred at room temperature for 2 h and quenched by additionof ice. The reaction mixture was diluted with EtOAc and washed with sat.NaHCO₃, sat. NaCl, dried over Na₂SO₄, filtered and concentrated toafford(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264)as clear oil (2.9 g, 100% yield). LCMS: RT=4.176 min [M+H] 632.2 (4 minPhenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA;

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264,2.70 g, 4.27 mmol) in DMF (6 mL) was added K₂CO₃ (1.47 g, 10.69 mmol),followed by isopropyl iodide (0.64 m, 6.40 mmol). The reaction mixturewas stirred at 60° C. for 16 h. The reaction mixture was filtered andthe solid was washed with EtOAc. The filtrate was washed with H₂O, sat.NaCl, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by ISCO silica gel column using 0 to 50% EtOAc inhexane as eluting solvents to yield(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 273)as white powder (2.4 g, 83% yield). LCMS: RT=4.05 min [M+H] 674.1(Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). ¹H NMR(400 MHz, CD₃OD) δ ppm 7.95-8.00 (2H, m), 7.42-7.47 (1H, m), 7.19 (1H,t, J=7.47 Hz), 7.12 (3H, t, J=7.25 Hz), 6.99-7.07 (3H, m), 6.71-6.81(4H, m), 6.14-6.41 (1H, m), 4.26-4.32 (1H, m, J=6.15, 6.15, 6.15, 6.15Hz), 4.12 (1H, d, J=13.18 Hz), 3.85 (1H, d, J=12.74 Hz), 1.23 (3H, d,J=6.15 Hz), 1.17 (3H, d, J=6.15 Hz).

Alternatively,(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide may beprepared by the following Procedures:

Procedure 179

To a solution of 4-fluoro-3-hydroxybenzoic acid (1.49 g, 9.55 mmol) inDCM (40 mL) was added TEA (1.2 mL, 8.61 mmol) followed byN,O-dimethylhydroxylamine hydrochloride (1.12 g, 11.5 mmol). Thereaction mixture was stirred at room temperature for 3 h, then dilutedwith DCM, washed with water twice, dried over Na₂SO₄, filtered andconcentrated to yield 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide asa colorless oil (1.90 g, 100% yield). LCMS: RT=0.89 min [M+H] 200.10(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

To a solution of 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (1.90 g,9.55 mmol) in DMF (8 mL) was added imidazole (740 mg, 10.8 mmol) andTBDMSCl (1.62 g, 10.8 mmol) at room temperature. The reaction mixturewas stirred for 48 h and quenched with saturated NaHCO₃. The solutionwas extracted with ether (3×) and the combined ether portions werewashed with LiCl (10%), dried over Na₂SO₄, filtered and concentrated.The resulting colorless oil was purified by ISCO chromatography (120 gcolumn) using hexanes/EtOAc (0-100% over 30 min) to give3-(tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide(RT=10-12 minutes) as a colorless oil (2.00 g, 67% yield). LCMS: RT=2.06min [M+H] 314.22 (Phenomenex Luna C18 column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 220 nm); NMR: 400 MHz ¹H (CDCl₃) 7.26 ppm, 2H, m; 7.02 ppm, 1H, m;3.50 ppm, 3H, s; 3.31 ppm, 3H, s; 0.97 ppm, 9H, s, 0.16 ppm, 6H, s.

At −78° C. under argon, to a solution of1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M incyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide(2.00 g, 6.38 mmol) was added in one portion and the reaction mixturewas stirred at −78° C. for 1.5 h. The pale yellow solution was pouredinto a 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used torinse the reaction flask. The aqueous phase was separated and extractedwith diethyl ether (20 mL). The combined ether portions were dried overNa₂SO₄, filtered and concentrated. The resulting oil was purified byISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30min) to give(3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneat a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min[M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); NMR: 400 MHz ¹H (CDCl₃) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm,2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.

A round bottom flask was charged with(3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone(2.09 g, 4.50 mmol), (R)-2-methylpropane-2-sulfinamide (653 mg, 5.4mmol), Ti(OEt)₄ (1.54 g, 6.76 mmol) and anhydrous THF (40 mL). Theresulting solution was heated at 75° C. under argon for 14 h. Thesolvents were removed and the residue was diluted with ether (50 mL) andsat. NaCl (20 mL). The resulting mixture was filtered through a glassfrit and the filtrate transferred to a separatory funnel. The organicportion was separated and the aqueous phase extracted with diethyl ether(2×20 mL). The combined organic portions were dried over Na₂SO₄,filtered and concentrated. The residue was dissolved in hexane:EtOAc andpurified by ISCO chromatography (2×120 g column) using hexanes/EtOAc(0-100% over 30 min) to yield(R)-N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamideat a retention time of 14 min (2.05 g, 80% yield) LCMS: RT=2.37 min[M+H] 568.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). NMR: 400 MHz ¹H (CDCl₃) 7.36 ppm, 1H, m; 7.11 ppm, 5H, m; 5.90 ppm,1H, t, J=52.73 Hz; 0.97 ppm, 9H, s; 0.18 ppm, 6H, s.

At −78° C. to a solution of(R)-N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(1.0 g, 1.76 mmol) in DCM (50 mL) was added BF₃.Et₂O (0.77 mL, 3.52mmol) via syringe. After 5 min, BnMgCl solution (3.5 mL, 1.0 M solutionin ether, 3.5 mmol) was added dropwise and the reaction mixture wasstirred at −78° C. for 1 h. An additional portion of BnMgCl (3.5 mL, 1.0M solution in ether, 3.5 mmol) was added dropwise and the reaction wasstirred for an additional 1 h at −78° C. The reaction mixture was pouredinto saturated NaCl (50 mL) and the organic layer was separated. Theaqueous layer was extracted with DCM (2×20 mL) and the combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The resultingoil was purified by ISCO chromatography (120 g column) usinghexanes/EtOAc (0-100% over 30 min) to give an approximate 4:1 mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideand(S)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideat a retention time of 12 min (824 mg, 71% yield) LCMS: RT=2.43 min[M+H] 660.39 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). The diastereomeric ratio of the product was determined to be 4:1 byChiral HPLC analysis (Chiralcel® AD, 90:10 heptane:i-PrOH, 1 mL/min, 254nm, RT (minor)=4.43 min, PA=17%; RT (major)=19.28 min, PA=71%) and thediastereomeric mixture was taken on directly to the next step, Procedure112, or the diastereomers were separated as described in Procedure 114.NMR: 400 MHz ¹H (CDCl₃) 7.30 ppm, 2H, m; 7.06 ppm, 5H, m; 6.85 ppm, 2H,m; 6.76 ppm, 1H, m; 6.62 ppm, 2H, m; 5.79 ppm, 1H, m; 4.13 ppm, 1H, s;3.84 ppm, 1H, m; 3.47 ppm, 1H, m; 1.12 ppm, 9H, s; 0.84 ppm, 9H, s; 0.01ppm, 6H, d, J=4.39 Hz.

At room temperature a solution of NaOMe (5 mL, 0.5 M solution in MeOH)was added to the 4:1 diastereomeric mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(801 mg, 1.22 mmol). The reaction mixture was stirred for 15 minutes,MeOH was removed then the residue dissolved in EtOAc (50 mL) andtransferred to a separation funnel. HCl (20 mL, 1.0 N solution) wasadded and the EtOAc layer was separated. The aqueous layer was extractedwith EtOAc (2×10 mL) and the combined organic layers were dried overNa₂SO₄, filtered and concentrated to yield(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white foam (578 mg, 87% yield). LCMS: RT=1.987 min [M+H] 546.35(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).

At rt to a solution of 4:1 diastereomeric mixture(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(578 mg, 1.06 mmol) in DMF (10 mL) was added K₂CO₃ (800 mg, 5.80 mmol)and the slurry was stirred vigorously. 2-Iodopropane (220 mg, 1.27 mmol)was added and the reaction mixture was stirred at rt for 16 h. Thereaction mixture was diluted with ether (50 mL), washed successivelywith 10% LiCl (2×20 mL) and water (20 mL). The organic portion was driedover Na₂SO₄, filtered and concentrated to yield(R)-N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a pale orange foam (780 mg, 100% yield).

The 4:1 diastereomeric mixture of(R)-N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(780 mg, 1.06 mmol crude) was separated by Chiral preparative HPLCchiralpak AD 20μ column, 5×50 cm, eluting with 30% IPA/Heptane with flowrate 50 mL/min.

(R)-N-((S)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 17 min and isolated as a colorless oil(101 mg, yield 16%). LCMS: RT=2.128 min [M+H] 588.38 (Phenomenex LunaC18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm); Chiral HPLC:RT=4.35 min, ee 100% (Diacel Chiralpak AD 10μ column, 4.6×250 mmisocratic elution with IPA (20%) and heptane; 1 mL/min, monitoring at254 nm).

(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 39 min and isolated and was isolatedas a colorless oil (398 mg, yield 64%). LCMS: RT=2.138 min [M+H] 588.38(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); ChiralHPLC: RT=9.98 min, ee 100% (Diacel Chiralpak AD 10μ column, 4.6×250 mmisocratic elution with IPA (20%) and heptane; 1 mL/min, monitoring at254 nm) NMR: 400 MHz ¹H (CDCl₃) 7.08 ppm, 5H, m; 6.84 ppm, 2H, d, J=7.47Hz; 6.77 ppm, 2H, d, J=7.47 Hz; 6.63 ppm, 2H, m; 5.79 ppm, 1H, t,J=52.95 Hz; 4.33 ppm, 1H, m; 4.15 ppm, 1H, s; 3.92 ppm, 1H, d, J=12.30Hz; 3.48 ppm, 1H, d, J=12.30 Hz; 1.22 ppm, 3H, d, J=6.15 Hz; 1.18 ppm,3H, d, J=5.71 Hz; 1.14 ppm, 9H, s.

To a solution of(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(398 mg, 0.678 mmol) in MeOH (1.5 mL) was added HCl (1.5 mL, 4 Msolution in dioxane) and the reaction mixture was stirred for 30 min.The reaction mixture was diluted with ether (50 mL) and the organiclayer was washed with sat. NaHCO₃ (20 mL), dried over Na₂SO₄, filteredand concentrated to give(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamineas a colorless oil (334 mg, 100% yield). LCMS: RT=1.76 min [M−NH₂]467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=3.04 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.15 ppm, 3H, m;6.99 ppm, 4H, m; 6.89 ppm, 1H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm,2H, d, J=6.15 Hz; 5.87 ppm, 1H, m; 4.42 ppm, 1H, m; 3.47 ppm, 2H, s;1.27 ppm, 6H, dd, J=7.91, 6.15 Hz.

Alternatively, the diastereomeric mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidecan be separated as described in Procedure 114 and the individualdiastereomers converted to (R) and(S)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamineby the methods described in Procedure 113.

The diastereomer mixture of(R)-N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(1.14 g, 1.73 mmol) was separated by Chiral preparative HPLC chiralpakAD 20μ column, 5×50 cm, eluting with 30% IPA/Heptane with flow rate 50mL/min.

(R)-N-((S)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 19 min (114 mg, yield 10%). LCMS:RT=2.45 min [M+H] 660.41 (Phenomenex Luna C18 column, 4.6×30 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm).

(R)-N-((R)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas eluted at a retention time of 36 min (634 mg, yield 56%). LCMS:RT=2.41 min [M+H] 660.39 (Phenomenex Luna C18 column, 4.6×30 mm elutingwith 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,monitoring at 220 nm); Chiral HPLC: RT=8.54 min, ee 100% (DiacelChiralpak AD 10 column, 4.6×250 mm isocratic elution with IPA (20%) andheptane; 1 mL/min, monitoring at 254 nm) NMR: 400 MHz ¹H (CDCl₃) 7.03ppm, 5H, m; 6.84 ppm, 2H, m; 6.74 ppm, 1H, d, J=8.79 Hz; 6.66 ppm, 1H,dd, J=8.13, 1.98 Hz; 6.61 ppm, 2H, m; 5.76 ppm, 1H, m; 4.12 ppm, 1H, s;3.90 ppm, 1H, d, J=12.74 Hz; 3.46 ppm, 1H, d, J=12.30 Hz; 1.11 ppm, 9H,s; 0.84 ppm, 9H, s; 0.01 ppm, 6H, d, J=4.83 Hz.

(R)-N-((R)-1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared from(R)-N-((R)-1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 112 in quantitative yield. LCMS: RT=1.998 min[M+H] 546.28 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm). HPLC: RT=3.83 min, Purity 98% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.61 ppm, 1H, s;7.40 ppm, 1H, dd, J=8.13, 1.98 Hz; 7.13 ppm, 3H, m; 6.99 ppm, 1H, dd,J=10.33, 8.57 Hz; 6.84 ppm, 3H, m; 6.68 ppm, 2H, m; 6.61 ppm, 1H, m;5.85 ppm, 1H, tt, J=52.95, 2.64 Hz; 4.30 ppm, 1H, s; 4.02 ppm, 1H, d,J=12.30 Hz; 3.50 ppm, 1H, d, J=12.30 Hz; 1.24 ppm, 9H, s.

(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas prepared from(R)-N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 6 in 78% yield. LCMS: RT=2.17 min [M+H] 588.17(Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm) HPLC:RT=4.20 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4 mL/min,monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.16 ppm, 3H, m; 7.10 ppm,2H, m; 6.87 ppm, 4H, m; 6.70 ppm, 2H, m; 5.86 ppm, 1H, m; 4.41 ppm, 1H,m; 4.31 ppm, 1H, s; 3.98 ppm, 1H, d, J=12.74 Hz; 3.56 ppm, 1H, d,J=12.74 Hz; 1.30 ppm, 3H, d, J=5.71 Hz; 1.25 ppm, 3H, d, J=6.15 Hz; 1.22ppm, 9H, s.

(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanaminewas prepared from(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas described in Procedure 6 in 97% yield. LCMS: RT=1.83 min [M−NH₂]467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90%MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220nm); HPLC: RT=3.17 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.2% PPA; 4mL/min, monitoring at 220 nm) NMR: 400 MHz ¹H (CDCl₃) 7.16 ppm, 3H, m;7.01 ppm, 3H, m; 6.92 ppm, 2H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm,2H, d, J=7.03 Hz; 5.86 ppm, 1H, m; 4.41 ppm, 1H, m; 3.49 ppm, 2H, s;1.25 ppm, 6H, m.

(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide may beprepared from(R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamineby the methods described in Procedure 7.

Alternatively,(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide may beprepared by the following procedures:

Procedure 180

To a 5 L four necked round bottom flask was added3-hydroxy-4-fluorobenzoic acid (100 g, 0.64 mol) and CH₂Cl₂ (2.3 L).Triethylamine (107 mL, 0.768 mol) was then added to the suspension. Thesolution was cooled to 78° C., and EDCI (184.2 g, 0.961 mol) was addedportion wise followed by the addition of N,O-dimethylhydroxyaminehydrochloride (93.6 g, 0.96 mol). The reaction mixture was stirred at−78° C. for 1 h and then allowed to warm to 0° C. over a period of 2 h.The reaction mixture was transferred to a separatory funnel and washedwater (2×1.2 L). The organic portion was dried over Na₂SO₄, filtered andconcentrated in vacuo to give4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a white solid (94.4 g,74%).

A 2 L round bottom flask equipped with a mechanical stirrer, a N₂ inlet,a condenser and a temperature controller, was charged4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (99.6 g, 0.5 mol),isopropyl iodide (110.5 g, 0.65 mol) and Cs₂CO₃ (195.5 g) and DMF (300mL). The reaction mixture was heated at 50° C. for 3 h. Isopropyl iodide(17.0 g, 0.1 mol) was added and the reaction was heated at 50° C. for 12h. The reaction mixture was allowed to cool to rt and water (1 L) andCH₂Cl₂ (500 mL) were added. The reaction mixture was stirred at rt for0.5 h, and the organic phase was separated. The aqueous layer wasextracted with CH₂Cl₂ (3×500 mL). The combined organic extracts werewashed with water (2×1 L), brine (1 L), dried over MgSO4, filtered andconcentrated in vacuo at 40° C. for 18 h to give4-fluoro-3-isopropoxy-N-methoxy-N-methlbenzamide as an off-white solid(120.0 g, 100%).

Procedure 181

A 3-liter four neck round-bottomed flask (flame dried) was charged1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (72.88 g, 0.25mol), 4-fluoro-3-isopropoxy-N-methoxy-N-methylbenzamide (60.39 g, 0.25mol) and dry THF (700 mL) under N₂. The solution was cooled to −76° C.,and a solution of n-BuLi in hexane (2.5M, 100 mL, 0.25 mol) wasdrop-wise maintaining the reaction mixture temperature below −70° C.over a period of 40 min. The reaction mixture was stirred at −76° C. for1.5 h then quenched with 1N HCl (500 mL). The mixture was concentratedin vacuo to half the volume and was partitioned between EtOAc and H₂O(v/v 1:0.3, 1 L). The organic phase was separated and the aqueous layerwas extracted with EtOAc (500 mL). The combined organic extracts werewashed with brine and then concentrated in vacuo to give a yellow oilwhich was purified by column chromatography using CH₂Cl₂ in hexanes (0%to 20%) to give(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneas a colorless oil contaminated with a by-product (49.0 g, 50%). LC-MS(10-90% MeOH in H₂O with 0.1% TFA in a 2-min gradient) 393.2 (M+H),retention time=2.15 min.

A solution of(4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone(49.0 g, 0.125 mol), (R)-(+)-2-methylpropane-2-sulfinamide (30.2 g, 0.25mol), and Ti(Oet)₄ (51.9 mL, 0.25 mol) in dry THF was heated to refluxunder N₂ for 20 h. After allowing to cool to rt, the reaction mixturewas poured into ice water (800 mL) with stirring. The reaction flask waswashed with small amount of EtOAc. The yellow suspension was thenfiltered through a Celite pad and the pad rinsed with EtOAc (ca. 500mL). The filtrate was concentrated in vacuo to remove most of THF (<30°C.). The remaining filtrate was partitioned between EtOAc and H₂O (1:1,1 L). The organic phase was separated and washed with brine (1 L). Afterconcentration in vacuo, the orange oily residue was dissolved in CH₂Cl₂(ca. 100 mL). The solution was purified by silica gel flash column usingEtOAc in Hexane (0-20%) to give(R,Z/E)-N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(24.4 g). The mixed fractions were subjected to an additional silica gelflash column to give an additional 9.9 g of(R,Z/E)-N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide.The residual mixed fraction (ca. 9.7 g) was dissolved in EtOAc in hexane(25%, 80 mL) and subjected to an additional silica gel flashchromatography column to give(R,Z/E)-N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide(6.90 g). Total yield: 41.2 g (67%). LC-MS (10-90% MeOH in H₂O with 0.1%TFA in a 4-min gradient) 496.1 (M+H), retention time=4.23 min.

Procedure 182

A flame dried 3 L round bottom flask equipped with a mechanical stirrer,a thermometer, a N₂ inlet and a dropping funnel, was charged a solutionof(R,Z/E)-N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyne)methylene)-2-methylpropane-2-ethylpropane-2-sulfinamide(40.5 g, 81.7 mol) in dry CH₂Cl₂ (1 L). The solution was cooled to −76°C. and BF₃Et₂O (12.3 mL, 90.0 mol, 1.2 eq) was added in one portion. Thereaction mixture was stirred at −76° C. for 15 min, and a solution ofphenyl magnesium chloride (1.0 M in ether, 105.7 mL, 105.7 mol) wasadded dropwise below −70° C. over a period of 1 h before the reactionmixture was quenched with brine (800 mL). The resulting solution wasstirred for 10 min, then transferred a 2 L separatory funnel. Theorganic phase was separated and the aqueous layer was extracted withCH₂Cl₂ (500 mL). The combined organic phases were dried over MgSO₄. Thesolution was filtered and concentrated to ca. 100 mL. The residue wasthen purified by silica gel column chromatography using 0-20% of EtOAcin hexanes to give a yellow oil (48.5 g, 100%). LC-MS (10-90% MeOH inH₂O with 0.1% TFA in a 4-min gradient) 588.3 (M+H), retention time=4.36min. Analytical chiral HPLC (AD column, 25% IPA in heptane with 0.01%DEA, isocratic), t_(R1)=4.16 min for(R)-N-((S)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide,t_(R2)=8.60 min for(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide.48.5 g of the diastereomeric mixture compound (4/1 ratio) was separatedby SFC on the Thar 350 system. A total of 33.5 g of(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(yield: 69.3%) was obtained. Chiral preparative conditions are listedhere.

Sample Preparation:

The sample is dissolved in IPA to a concentration of 110 mg/ml. at aconcentration of 50 mg/ml. Sample readily dissolves.

Preparative conditions on Thar SFC-350 column Chiralcel AD-H 5 × 25 cmmobile phase 20% IPA in CO₂ pressure (bar) 100 flow rate (ml/min) 240solution concentration (mg/ml) 110 injection amount (ml) 10 Cycle time(min/inj) 6.5 Temperature (° C.) 35 throughput (g/hr) 10 Detectorwavelength (nm) 254

(R)-N-((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas converted to(R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide as describedin 114.

Example 349A

(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideProcedure 183

(R)-4-fluoro-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 273) was converted to(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideas described in Procedure 59.(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamidewas subsequently converted to(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideby the methods described in Procedure 161.

Alternatively,(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidemay be prepared by the following Procedures:

Procedure 184

To a solution of(S)-N-((R)-1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideprepared as described in Procedure 3, 4, 5, 6 and 59 (0.545 g, 1 mmol)in CH₂Cl₂ (10 mL) was added Cu(OAc)₂ (0.182 g, 1 mmol), followed bypyridine (0.79 g, 10 mmol) and2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (0.159 g, 0.66 mmol). Thereaction mixture was stirred overnight under ambient air and filteredthrough a plug of celite and neutral alumina. The solid was washed withethyl acetate and the filtrate was concentrated under reduced pressureto yield(S)-N-((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenyl)-2-methylpropane-2-sulfinamideas an off-white foam (0.495 g, 87% yield). LCMS: RT=3.653 min [M+H]572.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueousacetonitrile containing 0.1% trifluoroacetic acid over a 4 minutegradient, monitoring at 220 nM). ¹H NMR (CDCl₃) ppm 7.2-7.1 (m, 5H),7.02 (d, J=6.2 Hz, 1H), 6.89 (d, J=6.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H),6.68 (br, 2H), 6.54 (dd, J=6.2 Hz, 13.6 Hz, 1H), 5.84 (t, J=52.7 Hz,1H), 4.62 (dd, J=2.2 Hz, 13.6 Hz, 1H), 4.40 (dd, J=2.2 Hz, 5.7 Hz, 1H),4.21 (s, 1H), 3.95 (d, J=12.8 Hz, 1H), 3.55 (d, J=12.7 Hz, 1H), 1.19 (s,9H).

Procedure 185

To an oven-dried 3-necked 25 mL RB flask under nitrogen was added CH₂Cl₂(3.5 mL) and 1 M diethylzinc solution in hexane (3.43 mL, 3.43 mmol).The flask was cooled in an ice-bath and a solution of trifluoroaceticacid (0.391 g, 3.43 mmol) in CH₂Cl₂ (1 mL) was added dropwise viasyringe. After stirring for 15 min, a solution of diiodomethane (0.918g, 3.43 mmol) in CH₂Cl₂ (1 mL) was added. The reaction mixture wasstirred at rt for 15 min, followed by addition of(S)-N-((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide(0.495 g, 0.87 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was allowedto warm to rt and stirred for 4 h. The reaction mixture was diluted withCH₂Cl₂ and washed successively with sat. sodium bicarbonate, water, sat.NaCl, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by ISCO using a gradient of 5-70%EtOAc/hexane as eluent to yield(S)-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideas a white foam (0.347 g, 71% yield). HPLC: RT=3.668 min [M+H] 586.3(Phenomenex Luna C18 5p column, eluting with 10-90% aqueous acetonitrilecontaining 0.1% trifluoroacetic acid over a 4 minute gradient,monitoring at 220 nm). ¹H NMR (CDCL₃) ppm 7.2-7.05 (m, 6H), 6.91 (d,J=6.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.71 (m, 2H), 5.84 (t, J=53.1 Hz,1H), 4.21 (s, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.62 (m, 1H), 3.56 (d,J=12.8 Hz, 1H), 1.22 (s, 9H), 0.72-0.65 (m, 4H).

Procedure 186

(S)-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamidewas converted to(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamideby the methods described in Procedures 6 and 7.

Alternatively,R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamidemay be prepared from(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideby the following methods:

Procedure 187

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(Example 264, 100 mg, 0.158 mmol) in toluene (0.2 ml) was added Na₂CO₃(25 mg, 0.235 mmol) and catalytic amount of [Ir(cod)Cl]₂ (2 mg),followed by vinyl acetate (68 mg, 0.79 mmol). The reaction mixture wasstirred at 100° C. for 16 h. The resulting mixture was filtered and thesolid was washed with CH₂Cl₂. The CH₂Cl₂ layer was washed with 1 N NaOH,H₂O and the organic portion dried over Na₂SO₄ and filtered. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column using 0 to 60% EtOAc in hexane to afford(R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamideeluting out at 20% EtOAc in hexane as colorless oil (80 mg, 77%). LCMS:RT=2.237 min [M+H] 658.3 (2 min Phenomenex Luna C18 column, 4.6×30 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5mL/min, monitoring at 220 nm. NMR: 400 MHz ¹H (CD₃OD) ppm 3.87 (d,J=12.74 Hz, 1H), 4.05-4.15 (m, 1H), 4.35 (dd, J=5.93, 1.98 Hz, 1H), 4.55(dd, J=13.84, 1.98 Hz, 1H), 6.12-6.41 (m, 1H), 6.48 (dd, J=13.62, 6.15Hz, 1H), 6.72 (d, J=7.03 Hz, 2H), 6.87-7.24 (m, 9H), 7.37-7.51 (m, 1H),7.88-8.04 (m, 2H).

Procedure 188

To a solution of(R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide(66 mg, 0.10 mmol) in 0.5 ml toluene was added Et₂Zn (1 N, 0.2 ml, 0.2mmol), followed by CH₂I₂ (16 ml, 0.2 mmol). The reaction mixture wasstirred at 120° C. for 3 h. The reaction mixture was quenched byaddition of 1 N HCl and the aqueous layer was extracted with CH₂Cl₂. Theorganic layer was washed with sat. NaHCO₃ and concentrated under reducedpressure. The resulting residue was purified by ISCO silica gel columnusing 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC(phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H₂Oover 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) toafford(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide(Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm elutingwith 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min,monitoring at 220 nm. NMR: 400 MHz ¹H (CDCl₃) ppm 0.45-0.73 (m, 4H),3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H),6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m,5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).

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It is noted that the proceeding examples, while illustrative of thepresent invention, are not in sequential order and some example numbersmay be missing.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20120322761A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of formula Ia or Ib

or stereoisomers or prodrugs or pharmaceutically acceptable salt formsthereof, wherein: A is phenyl, which is substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)═O, 17) —S(O)_(p)R₆, 18) —SO₂NHR₆, 19) —COOR₆, 20) —NHC(CN)NHR₆, 21)—CONR₆R₆, 22) (C₂-C₆)-alkynyl, which may be optionally substituted withone or more R₂₀'s, 23) (C₂-C₆)-alkenyl, which may be optionallysubstituted with one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆, 26)—OCONR₆R₆, or 27) cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or any two adjacent substituents may join together toform a 4- to 8-membered ring, which optionally may contain 1-4heteroatoms selected from N, O, and S and be optionally substituted withone or more R₂₀'s; B is: (a) phenyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20)—CONR₆R₆; and 21) cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or (b) heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17)—SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆; and 21)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;C is: (a) alkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆,15) —SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (b) alkenyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl; and 15) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; or (d) heterocyclo, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; R₁ is H, —C(O)NR₂R₃,—C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₈, or —C(S)R₃; R₂ is: (a) H; (b)alkyl, which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19)—NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; (c) alkenyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19)—S(O)_(p)R₆, 20) —SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (d) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19)(C₂-C₆)-alkenyl, 20) (C₂-C₆)-alkynyl; and 21) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; R₃ is: (a) alkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆,19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionallysubstituted with one or more R₂₀'s; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) —(C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (f) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆,20) —SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or R₂ and R₃ aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₄ is: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) (C₂-C₆)-alkenyl; or (e) (C₂-C₆)-alkynyl; R₅ is arylalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;R₆, at each occurrence, is independently: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, which maybe optionally substituted with one or more R₂₀'s; (c) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; (e) heterocyclyl, other than heteroaryl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₉R₁₀, 9) aryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₂₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₇ is aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; R₈ canindependently be: (a) H; (b) alkyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 10) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) —(C₂-C₆)-alkynyl, 17)—COR₂₆, 18) —S(O)_(p)R₂₆, 19) —SO₂NHR₂₆, 20) —COOR₂₆, 21) —NHC(CN)NHR₂₆;and 22) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (c) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (d) cycloalkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (e) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; or (f) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₈'s aretaken together to form a 3- to 9-membered ring, which may optionallycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₉ and R₁₀ are independently: (a)hydrogen; (b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R₂₀'s; (c)—[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may be optionallysubstituted with one or more R₂₀'s; (d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl optionally substituted with one or more R₂₀'s; (f)—CONR₂₆R₂₆; (g) —(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j)—SO₂NHR₂₆; (k) —COOR₂₆; (l) —NHC(CN)NHR₂₆; or m)—[(C═O)O_(r)]_(s)cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or R₉ and R₁₀ are taken together with the nitrogen towhich both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₂₀'s; R₂₀ is: (a) halo; (b)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) ═O; (q) —(C₂-C₆)-alkynyl; (r) —COR₂₆; (s)—S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u) —COOR₂₆; (v) —NHC(CN)NHR₂₆; (w)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(x) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (y) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s)cycloalkyl; (t) cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w)—SO₂NHR₂₆; (x) —COOR₂₆; or (y) —NHC(CN)NHR₂₆; R₂₆, at each occurrence,is independently: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with oneor more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆; and 23)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17)—CONR₃₆R₃₆, 18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆,22) —SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₄₀'s; (d) heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₄₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; or two R₂₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₄₀'s; R₂₉ and R₃₀ are independentlyhydrogen, —[(C═O)O_(r)]_(s)aryl, —[(C═O)O_(r)]_(s)alkenyl,—[(C═O)O_(r)]_(s)alkyl, heterocyclyl, alkynyl, —COR₃₆, —S(O)_(p)R₃₆,—SO₂NHR₃₆, —COOR₃₆, —C(CN)NHR₃₆, or cycloalkyl, wherein the aryl, alkyl,alkenyl, cycloalkyl or heterocyclyl may be optionally substituted withone or more R₄₀'s; or R₂₉ and R₃₀ are taken together with the nitrogento which both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₄₀'s; R₃₆, at each occurrence,is independently alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl,other than heteroaryl, wherein the alkyl, aryl, cycloalkyl, heteroarylor heterocyclyl may be optionally substituted with one or more R₄₀'s;R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉,—S(O)_(p)R₄₉, —SO₂NHR₄₉, —COOR₄₉, or —NHC(CN)NHR₄₉; R₄₉ and R₅₀, at eachoccurrence, are independently hydrogen, alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl; r is 0 to 5; s is 0to 4; and p is 1 or 2; excluding compounds having the following formula:


2. A compound of claim 1, wherein the compound is a compound of formulaIa


3. A compound of claim 1, wherein: A is phenyl, which is substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—COR₆, 16) ═O, 17) —S(O)_(p)R₆, 18) —SO₂NHR₆, 19) —COOR₆, 20)—NHC(CN)NHR₆, 21) —CONR₆R₆, 22) (C₂-C₆)-alkynyl, which may be optionallysubstituted with one or more R₂₀'s, 23) (C₂-C₆)-alkenyl, which may beoptionally substituted with one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆,or 26) —OCONR₆R₆; or any two adjacent substituents may join together toform a 4- to 8-membered ring, which optionally may contain 1-4heteroatoms selected from N, O, and S and be optionally substituted withone or more R₂₀'s; B is: (a) phenyl, which is substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆; or (b) heteroaryl, which is substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆; C is: (a) alkyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆,15) —SO₂NHR₆, 16) —COOR₆, and 17) —NHC(CN)NHR₆; (b) alkenyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl; or (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, and 17) —NHC(CN)NHR₆; R₁ is H, —C(O)NR₂R₃,—C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₈, or —C(S)R₃; R₂ is: (a) H; (b)alkyl, which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, and 19)—NHC(CN)NHR₆; (c) alkenyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆,20) —SO₂NHR₆, 21) —COOR₆, and 22) —NHC(CN)NHR₆; or (d) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16)—COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, and20) (C₂-C₆)-alkynyl; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆,and 19) —NHC(CN)NHR₆; (b) aryl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (c)cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (e)heterocyclyl, other than heteroaryl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆,20) —S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; or (f)alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆,20) —SO₂NHR₆, 21) —COOR₆, and 22) —NHC(CN)NHR₆; or R₂ and R₃ are takentogether to form a 3- to 9-membered ring, which optionally may contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s; R₄ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (b) aryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (c)cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; (d)(C₂-C₆)-alkenyl; or (e) (C₂-C₆)-alkynyl; R₅ is arylalkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, and 23) —NHC(CN)NHR₆; R₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (f)hydrogen; (g) alkynyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₉R₁₀, 9) aryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₂₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₇ is aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆; R₈ can independentlybe: (a) H; (b) alkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17)—COR₂₆, 18) —S(O)_(p)R₂₆, 19) —SO₂NHR₂₆, 20) —COOR₂₆, and 21)—NHC(CN)NHR₂₆; (c) aryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23)—NHC(CN)NHR₂₆; (d) cycloalkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23)—NHC(CN)NHR₂₆; (e) heteroaryl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23)—NHC(CN)NHR₂₆; or (f) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, and 23) —NHC(CN)NHR₂₆; or two R₈'s are takentogether to form a 3- to 9-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s; R₉ and R₁₀ are independently: (a) hydrogen; (b)—[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionally substitutedwith one or more R₂₀'s; (c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, whereinthe alkenyl may be optionally substituted with one or more R₂₀'s; (d)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; (e) heterocyclyl optionallysubstituted with one or more R₂₀'s; (f) —CONR₂₆R₂₆; (g)—(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j) —SO₂NHR₂₆; (k)—COOR₂₆; or (l) —NHC(CN)NHR₂₆; or R₉ and R₁₀ are taken together with thenitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R₂₀'s; R₂₀ is: (a) halo;(b) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) ═O; (q) —(C₂-C₆)-alkynyl; (r) —COR₂₆; (s)—S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u) —COOR₂₆; (v) —NHC(CN)NHR₂₆; (w)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(x) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (y) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s)cycloalkyl; (t) cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w)—SO₂NHR₂₆; (x) —COOR₂₆; or (y) —NHC(CN)NHR₂₆; R₂₆, at each occurrence,is independently: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with oneor more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b)aryl, which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17)—CONR₃₆R₃₆, 18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆,22) —SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (f)hydrogen; (g) alkynyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₄₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; or two R₂₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₄₀'s; R₂₉ and R₃₀ are independentlyhydrogen, —[(C═O)O_(r)]_(s)aryl, —[(C═O)O_(r)]_(s)alkenyl,—[(C═O)O_(r)]_(s)alkyl, heterocyclyl, alkynyl, —COR₃₆, —S(O)_(p)R₃₆,—SO₂NHR₃₆, —COOR₃₆, or —C(CN)NHR₃₆, wherein the aryl, alkyl, alkenyl orheterocyclyl may be optionally substituted with one or more R₄₀'s; orR₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s; R₃₆, at each occurrence, is independently alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl, other than heteroaryl,wherein the alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl may beoptionally substituted with one or more R₄₀'s; R₄₀ is halo, —OH, alkyl,alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl,haloalkyloxy, —CONR₄₉R₅₀, alkenyl, arylalkyloxy, ═O, alkynyl,cycloalkyl, cycloalkylalkyl, —COR₄₉, —S(O)_(p)R₄₉, —SO₂NHR₄₉, —COOR₄₉,or —NHC(CN)NHR₄₉; R₄₉ and R₅₀, at each occurrence, are independentlyhydrogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, otherthan heteroaryl; r is 0 to 5; s is 0 to 4; and p is 1 or
 2. 4. Acompound of claim 1, wherein: A is phenyl, which is substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)═O, 17) —COOR₆, 18) —CONR₆R₆, 19) (C₂-C₆)-alkynyl, which may beoptionally substituted with one or more R₂₀'s, 20) (C₂-C₆)-alkenyl,which may be optionally substituted with one or more R₂₀'s, 21) —OCOR₆,22) —OCOOR₆, or 23) —OCONR₆R₆; or any two adjacent substituents may jointogether to form a 4- to 8-membered ring, which optionally may contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s; B is: (a) phenyl, which is substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—COOR₆, and 17) —CONR₆R₆; or (b) a nitrogen containing heteroaryl, whichis substituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —COOR₆, and 17)—CONR₆R₆; C is alkyl, which is substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OR₆, 3) —NR₉R₁₀, 4)aryl, which may be optionally substituted with one or more R₂₀'s, 5)heteroaryl, which may be optionally substituted with one or more R₂₀'s,6) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 7) —CONR₆R₆, and 8) —COOR₆; R₁ is —C(O)NR₂R₃, —C(O)OR₄ or —CH₂R₈;R₂ is: (a) H; (b) alkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, and 16) —COOR₆; (c) alkenyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, and 19) —COOR₆; or (d)cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CO(C₁-C₆)-alkyl, 16) —COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19)(C₂-C₆)-alkenyl, and 20) (C₂-C₆)-alkynyl; R₃ is: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (d) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio,5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;or (f) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, and 19) —COOR₆; orR₂ and R₃ are taken together to form a 3- to 9-membered ring, whichoptionally may contain 1-4 heteroatoms selected from N, O, and S and maybe optionally substituted with one or more R₂₀'s; R₄ is: (a) alkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; or (c) cycloalkyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; R₆, at each occurrence, is independently: (a) alkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; or two R₆'s are taken together to form a 3- to 9-memberedring, which optionally may contain 1-4 heteroatoms selected from N, O,and S and may be optionally substituted with one or more R₂₀'s; R₈ canindependently be: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17)—COR₂₆, and 18) —COOR₂₆; (b) aryl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; (c) cycloalkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; or (e) heterocyclyl, other than heteroaryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; ortwo R₈'s are taken together to form a 3- to 9-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and may beoptionally substituted with one or more R₂₀'s; R₉ and R₁₀ areindependently: (a) hydrogen; (b) —[(C═O)O_(r)]_(s)aryl, wherein the arylmay be optionally substituted with one or more R₂₀'s; (c)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; or (d) heterocyclyl optionallysubstituted with one or more R₂₀'s; or R₉ and R₁₀ are taken togetherwith the nitrogen to which both are attached to form a 3- to 8-memberedring, which may optionally contain 1-4 heteroatoms selected from N, O,and S and be optionally substituted with one or more R₂₀'s; R₂₀ is: (a)halo; (b) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COOR₂₆; (s)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(t) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (u) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl;(s) cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆; R₂₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₄₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₄₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; or two R₂₆'s are taken together to form a 3- to 9-memberedring, which optionally may contain 1-4 heteroatoms selected from N, O,and S and be optionally substituted with one or more R₄₀'s; R₂₉ and R₃₀are independently hydrogen, —[(C═O)O_(r)]_(s)aryl,—[(C═O)O_(r)]_(s)alkyl, or heterocyclyl, wherein the aryl, alkyl orheterocyclyl may be optionally substituted with one or more R₄₀'s; orR₂₉ and R₃₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₄₀'s; R₃₆, at each occurrence, is independently alkyl,aryl, cycloalkyl, heteroaryl or heterocyclyl, other than heteroaryl,wherein the alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl may beoptionally substituted with one or more R₄₀'s; R₄₀ is halo, —OH, alkyl,alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl,haloalkyloxy, —CONR₄₉R₅₀, alkenyl, arylalkyloxy, ═O, alkynyl,cycloalkyl, cycloalkylalkyl, —COR₄₉ or —COOR₄₉; R₄₉ and R₅₀, at eachoccurrence, are independently hydrogen, alkyl, aryl, heteroaryl orheterocyclyl, other than heteroaryl; r is 0 to 3; s is 0 to 2; and p is1 or
 2. 5. A compound of claim 1, wherein: A is phenyl, which issubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17) —COOR₆,18) —CONR₆R₆, 19) (C₂-C₆)-alkynyl, which may be optionally substitutedwith one or more R₂₀'s, 20) —OCOR₆, 21) —OCOOR₆, or 22) —OCONR₆R₆; orany two adjacent substituents may join together to form a 4- to8-membered ring, which optionally may contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R₂₀'s; Bis: (a) phenyl, which is substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COOR₆, and 16)—CONR₆R₆; or (b) a 6- to 10-membered nitrogen containing heteroaryl,which is substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COOR₆, and 16) —CONR₆R₆; Cis alkyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OR₆, 3) —NR₉R₁₀, 4) aryl,which may be optionally substituted with one or more R₂₀'s, 5) anitrogen containing heteroaryl, which may be optionally substituted withone or more R₂₀'s, 6) —CONR₆R₆, and 7) —COOR₆; R₁ is —C(O)NR₂R₃, or—CH₂R₈; R₂ is: (a) H; (b) alkyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 10) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, and 16) —COOR₆; or (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16)—COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, and20) (C₂-C₆)-alkynyl; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (d) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio,5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;or (f) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, and 19) —COOR₆; orR₂ and R₃ are taken together to form a 3- to 9-membered ring, whichoptionally may contain 1-4 heteroatoms selected from N, O, and S and maybe optionally substituted with one or more R₂₀'s; R₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; or two R₆'s are taken together to form a 3- to 9-memberedring, which optionally may contain 1-4 heteroatoms selected from N, O,and S and may be optionally substituted with one or more R₂₀'s; R₈ canindependently be: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17)—COR₂₆, and 18) —COOR₂₆; (b) aryl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; (c) cycloalkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; or (e) heterocyclyl, other than heteroaryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; ortwo R₈'s are taken together to form a 3- to 9-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and may beoptionally substituted with one or more R₂₀'s; R₉ and R₁₀ areindependently: (a) hydrogen, (b) —[(C═O)O_(r)]_(s)aryl, wherein the arylmay be optionally substituted with one or more R₂₀'s, or (c)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; or R₉ and R₁₀ are taken togetherwith the nitrogen to which both are attached to form a 3- to 8-memberedring, which may optionally contain 1-4 heteroatoms selected from N, O,and S and be optionally substituted with one or more R₂₀'s; R₂₀ is: (a)halo; (b) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COOR₂₆; (s)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(t) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (u) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl;(s) cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆; R₂₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₄₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₄₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; or two R₂₆'s are taken together to form a 3- to 9-memberedring, which optionally may contain 1-4 heteroatoms selected from N, O,and S and be optionally substituted with one or more R₄₀'s; R₂₉ and R₃₀are independently hydrogen, —[(C═O)O_(r)]_(s)aryl, or—[(C═O)O_(r)]_(s)alkyl, wherein the aryl or alkyl may be optionallysubstituted with one or more R₄₀'s; or R₂₉ and R₃₀ are taken togetherwith the nitrogen to which both are attached to form a 3- to 8-memberedring, which may optionally contain 1-4 heteroatoms selected from N, O,and S and be optionally substituted with one or more R₄₀'s; R₃₆, at eachoccurrence, is independently alkyl, aryl, cycloalkyl, heteroaryl orheterocyclyl, other than heteroaryl, wherein the alkyl, aryl,cycloalkyl, heteroaryl or heterocyclyl may be optionally substitutedwith one or more R₄₀'s; R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio,cyano, nitro, —NR₄₉R₅₀, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀,alkenyl, arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉or —COOR₄₉; R₄₉ and R₅₀, at each occurrence, are independently hydrogen,alkyl, aryl or heteroaryl; r is 0 to 2; s is 0 to 1; and p is 1 or
 2. 6.A compound of claim 1, wherein: A is phenyl, which is substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)═O, 17) —COOR₆, 18) (C₂-C₆)-alkynyl, which may be optionally substitutedwith one or more R₂₀'s, 19) —OCOR₆, and 20) —OCOOR₆; or any two adjacentsubstituents may join together to form a 4- to 8-membered ring, whichoptionally may contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₂₀'s; B is: (a) phenyl, whichis substituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, and 15) —COOR₆; or (b) a6-membered nitrogen containing heteroaryl, which is substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, and 15)—COOR₆; C is alkyl, which is substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) phenyl, which may beoptionally substituted with one or more R₂₀'s, or 3) a 5- or 6-memberednitrogen containing heteroaryl, which may be optionally substituted withone or more R₂₀'s; R₁ is —C(O)NR₂R₃, or —CH₂R₈; R₂ is: (a) H; or (b)alkyl, which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, and 16) —COOR₆; R₃ is: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (d) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; or (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio,5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) —(C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; R₆, at each occurrence, is independently: (a) alkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; R₈ can independently be: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) aryl(C₂-C₆)-alkynyl, 14)—CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; (c) cycloalkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; or (e) heterocyclyl, other than heteroaryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; ortwo R₈'s are taken together to form a 3- to 9-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and may beoptionally substituted with one or more R₂₀'s; R₉ and R₁₀ areindependently: (a) hydrogen; or (b) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R₂₀'s;or R₉ and R₁₀ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s; R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl, which maybe optionally substituted with one or more R₂₁'s; (c) —OR₂₆; (d)(C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl, whichmay be optionally substituted with one or more R₂₁'s; (i) arylalkyl,which may be optionally substituted with one or more R₂₁'s; (j)heteroaryl, which may be optionally substituted with one or more R₂₁'s;(k) heteroarylalkyl, which may be optionally substituted with one ormore R₂₁'s; (l) heterocyclyl, which may be optionally substituted withone or more R₂₁'s; (m) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COOR₂₆; (s)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(t) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (u) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl;(s) cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆; R₂₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₄₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₄₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; R₂₉ and R₃₀ are independently hydrogen or—[(C═O)O_(r)]_(s)alkyl, wherein the alkyl may be optionally substitutedwith one or more R₄₀'s; or R₂₉ and R₃₀ are taken together with thenitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R₄₀'s; R₃₆, at eachoccurrence, is independently alkyl, aryl, cycloalkyl, heteroaryl orheterocyclyl, other than heteroaryl, wherein the alkyl, aryl,cycloalkyl, heteroaryl or heterocyclyl may be optionally substitutedwith one or more R₄₀'s; R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio,cyano, nitro, —NR₄₉R₅₀, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀,alkenyl, arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉or —COOR₄₉; R₄₉ and R₅₀, at each occurrence, are independently hydrogen,alkyl, aryl or heteroaryl; r is 0 to 2; s is 0 to 1; and p is 1 or
 2. 7.A compound of claim 1, wherein: A is phenyl, which is substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)═O, 17) (C₂-C₆)-alkynyl, which may be optionally substituted with one ormore R₂₀'s, and 18) —OCOR₆; or any two adjacent substituents may jointogether to form a 4- to 8-membered ring, which optionally may contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R₂₀'s; B is phenyl, which is substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl; C isalkyl, which is substituted with one or more substituents selected fromthe group consisting of: 1) phenyl, which may be optionally substitutedwith one or more R₂₀'s, or 2) a 5- or 6-membered nitrogen containingheteroaryl, which may be optionally substituted with one or more R₂₀'s;R₁ is —C(O)NHR₃ or —CH₂R₈; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; (d) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20)—COOR₆; or (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;R₆, at each occurrence, is independently: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; R₈ can independently be: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) aryl(C₂-C₆)-alkynyl, 14)—CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17) —COR₂₆, and 18) —COOR₂₆;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; (c) cycloalkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; or (e) heterocyclyl, other than heteroaryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; R₉and R₁₀ are independently: (a) hydrogen; or (b)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl,which may be optionally substituted with one or more R₂₁'s; (c) —OR₂₆;(d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h) aryl,which may be optionally substituted with one or more R₂₁'s; (i)arylalkyl, which may be optionally substituted with one or more R₂₁'s;(j) heteroaryl, which may be optionally substituted with one or moreR₂₁'s; (k) heteroarylalkyl, which may be optionally substituted with oneor more R₂₁'s; (l) heterocyclyl, which may be optionally substitutedwith one or more R₂₁'s; (m) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COOR₂₆; (s)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(t) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (u) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl;(s) cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆; R₂₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₄₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₄₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, and 22) —NHC(CN)NHR₃₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, and 24) —NHC(CN)NHR₃₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; (d)heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25)—NHC(CN)NHR₃₆; (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, and 25) —NHC(CN)NHR₃₆; or (f)hydrogen; R₂₉ and R₃₀ are independently hydrogen or—[(C═O)O_(r)]_(s)alkyl, wherein the alkyl may be optionally substitutedwith one or more R₄₀'s; R₃₆, at each occurrence, is independently alkyl,aryl, heteroaryl or heterocyclyl, other than heteroaryl, wherein thealkyl, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith one or more R₄₀'s; R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio,cyano, nitro, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, haloalkyl, haloalkyloxy, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl or cycloalkylalkyl; r is 0 to 2; sis 0 to 1; and p is 1 or
 2. 8. A compound of claim 1, wherein: A isphenyl, which is substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)=0, and 17)—OCOR₆; or any two adjacent substituents may join together to form a 4-to 8-membered ring, which optionally may contain 1-4 heteroatomsselected from N, O, and S and be optionally substituted with one or moreR₂₀'s; B is phenyl, which is substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl; C is methyl, which issubstituted with one or more substituents selected from the groupconsisting of: 1) phenyl, which may be optionally substituted with oneor more R₂₀'s, or 2) a 5- or 6-membered nitrogen containing heteroaryl,which may be optionally substituted with one or more R₂₀'s; R₁ is—C(O)NHR₃ or —CH₂R₈; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio,5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, and 16) —COOR₆; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆,and 20) —COOR₆; (d) heteroaryl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—CONR₆R₆, 16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆,and 20) —COOR₆; or (e) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, and 20) —COOR₆;R₆, at each occurrence, is independently: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —SO₂NHR₃₆, 20) —COOR₃₆, and 21)—NHC(CN)NHR₃₆; (b) aryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted with oneor more R₂₀'s, 10) arylalkyl, which may be optionally substituted withone or more R₂₀'s, 11) heteroaryl, which may be optionally substitutedwith one or more R₂₀'s, 12) heteroarylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclyl, which may beoptionally substituted with one or more R₂₀'s, 14) heterocyclylalkyl,which may be optionally substituted with one or more R₂₀'s, 15)halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)(C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —SO₂NHR₃₆, 22) —COOR₃₆, and 23)—NHC(CN)NHR₃₆; (c) heteroaryl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)nitro, 8) —NR₉R₁₀, 9) aryl, which may be optionally substituted with oneor more R₂₀'s, 10) arylalkyl, which may be optionally substituted withone or more R₂₀'s, 11) heteroaryl, which may be optionally substitutedwith one or more R₂₀'s, 12) heteroarylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclyl, which may beoptionally substituted with one or more R₂₀'s, 14) heterocyclylalkyl,which may be optionally substituted with one or more R₂₀'s, 15)halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19)═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —SO₂NHR₃₆, 23) —COOR₃₆, and 24)—NHC(CN)NHR₃₆; or (d) hydrogen; R₈ can independently be: (a) alkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3)—OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) (C₂-C₆)-alkynyl, 17)—COR₂₆, and 18) —COOR₂₆; (b) aryl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6)nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionally substituted with oneor more R₂₀'s, 9) arylalkyl, which may be optionally substituted withone or more R₂₀'s, 10) heteroaryl, which may be optionally substitutedwith one or more R₂₀'s, 11) heteroarylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 12) heterocyclyl, which may beoptionally substituted with one or more R₂₀'s, 13) heterocyclylalkyl,which may be optionally substituted with one or more R₂₀'s, 14)halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18)(C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, and 20) —COOR₂₆;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; or (e) heterocyclyl, other than heteroaryl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3)—OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl,which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, and 20) —COOR₂₆; R₉ and R₁₀ are independently: (a) hydrogen; or(b) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R₂₀'s; R₂₀ is: (a) halo; (b) (C₁-C₆)-alkyl;(c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀;(h) aryl, which may be optionally substituted with one or more R₂₁'s;(i) arylalkyl, which may be optionally substituted with one or moreR₂₁'s; (j) heteroaryl, which may be optionally substituted with one ormore R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) —(C₂-C₆)-alkynyl; (q) —COR₂₆; (r) —COOR₂₆; (s)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(t) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (u) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) (C₂-C₆)-alkynyl; (r) cycloalkyl;(s) cycloalkylalkyl; (t) —COR₂₆; or (u) —COOR₂₆; R₂₆, at eachoccurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₄₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₄₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —SO₂NHR₃₆, 20) —COOR₃₆, and 21)—NHC(CN)NHR₃₆; (b) aryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted withone or more R₄₀'s, 10) arylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 11) heteroaryl, which may be optionallysubstituted with one or more R₄₀'s, 12) heteroarylalkyl, which may beoptionally substituted with one or more R₄₀'s, 13) heterocyclyl, whichmay be optionally substituted with one or more R₄₀'s, 14)heterocyclylalkyl, which may be optionally substituted with one or moreR₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆, 18) ═O, 19)(C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —SO₂NHR₃₆, 22) —COOR₃₆, and 23)—NHC(CN)NHR₃₆; (c) heteroaryl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7)nitro, 8) —NR₂₉R₃₀, 9) aryl, which may be optionally substituted withone or more R₄₀'s, 10) arylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 11) heteroaryl, which may be optionallysubstituted with one or more R₄₀'s, 12) heteroarylalkyl, which may beoptionally substituted with one or more R₄₀'s, 13) heterocyclyl, whichmay be optionally substituted with one or more R₄₀'s, 14)heterocyclylalkyl, which may be optionally substituted with one or moreR₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17) —COOH, 18)—CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22) —SO₂NHR₃₆, 23)—COOR₃₆, and 24) —NHC(CN)NHR₃₆; or (d) hydrogen; R₂₉ and R₃₀ areindependently hydrogen or —[(C═O)O_(r)]_(s)alkyl, wherein the alkyl maybe optionally substituted with one or more R₄₀'s; R₃₆, at eachoccurrence, is independently alkyl, aryl or heteroaryl, wherein thealkyl, aryl or heteroaryl may be optionally substituted with one or moreR₄₀'s; R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,haloalkyl, haloalkyloxy, alkenyl, arylalkyloxy, ═O, alkynyl, cycloalkylor cycloalkylalkyl; r is 0 to 2; and s is 0 to
 1. 9. A compound of claim1, wherein: A is phenyl, which is substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, and 15) —COR₆;B is phenyl, which is substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl; C is methyl, which issubstituted with a 5- or 6-membered nitrogen containing heteroaryl,which may be optionally substituted with one or more R₂₀'s; R₁ is—C(O)NHR₃ or —CH₂R₈; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio,5) cyano, 6) nitro, 7) aryl, which may be optionally substituted withone or more R₂₀'s, 8) heteroaryl, which may be optionally substitutedwith one or more R₂₀'s, 9) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 10) halo(C₁-C₆)alkyl, 11)(C₂-C₆)-alkenyl, 12) (C₂-C₆)-alkynyl, 13) —COR₆, and 14) —COOR₆; (b)aryl, which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3)—OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may beoptionally substituted with one or more R₂₀'s, 8) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 9) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 10)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 11) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 12) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₆, and 17) —COOR₆; (c) cycloalkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be optionallysubstituted with one or more R₂₀'s, 8) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 11)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₆, and 17) —COOR₆; (d) heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be optionallysubstituted with one or more R₂₀'s, 8) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 11)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₆, and 17) —COOR₆; or (e) heterocyclyl, otherthan heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7)aryl, which may be optionally substituted with one or more R₂₀'s, 8)arylalkyl, which may be optionally substituted with one or more R₂₀'s,9) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 11) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —COR₆, and 17) —COOR₆; R₆, ateach occurrence, is independently: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) —COOH, 14) (C₂-C₆)-alkynyl,15) —COR₃₆, and 16) —COOR₃₆; or (b) hydrogen; R₈ can independently be:(a) alkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)aryl, which may be optionally substituted with one or more R₂₀'s, 8)heteroaryl, which may be optionally substituted with one or more R₂₀'s,9) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 10) halo(C₁-C₆)alkyl, 11) (C₂-C₆)-alkenyl, 12) (C₂-C₆)-alkynyl,13) —COR₂₆, and 14) —COOR₂₆; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be optionallysubstituted with one or more R₂₀'s, 8) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 11)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₂₆, and 17) —COOR₂₆; (c) cycloalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be optionallysubstituted with one or more R₂₀'s, 8) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 11)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₂₆, and 17) —COOR₂₆; (d) heteroaryl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, 3) —OR₂₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) aryl, which may be optionallysubstituted with one or more R₂₀'s, 8) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 11)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14) (C₂-C₆)-alkenyl, 15)(C₂-C₆)-alkynyl, 16) —COR₂₆, and 17) —COOR₂₆; or (e) heterocyclyl, otherthan heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)aryl, which may be optionally substituted with one or more R₂₀'s, 8)arylalkyl, which may be optionally substituted with one or more R₂₀'s,9) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 11) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 13) halo(C₁-C₆)alkyl, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —COR₂₆, and 17) —COOR₂₆; R₂₀is: (a) halo; (b) (C₁-C₆)-alkyl; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e)cyano; (f) nitro; (g) aryl, which may be optionally substituted with oneor more R₂₁'s; (h) arylalkyl, which may be optionally substituted withone or more R₂₁'s; (i) heteroaryl, which may be optionally substitutedwith one or more R₂₁'s; (j) heteroarylalkyl, which may be optionallysubstituted with one or more R₂₁'s; (k) heterocyclyl, which may beoptionally substituted with one or more R₂₁'s; (l) heterocyclylalkyl,which may be optionally substituted with one or more R₂₁'s; (m)halo(C₁-C₆)alkyl; (n) (C₂-C₆)-alkenyl; (o) —(C₂-C₆)-alkynyl; (p) —COR₂₆;(q) —COOR₂₆; (r) cycloalkyl, which may be optionally substituted withone or more R₂₁'s; or (s) cycloalkylalkyl, which may be optionallysubstituted with one or more R₂₁'s; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl;(c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) aryl; (h)arylalkyl; (i) heteroaryl; (j) heteroarylalkyl; (k) heterocyclyl; (l)heterocyclylalkyl; (m) halo(C₁-C₆)alkyl; (n) (C₂-C₆)-alkenyl; (o)(C₂-C₆)-alkynyl; (p) cycloalkyl; (q) cycloalkylalkyl; (r) —COR₂₆; or (s)—COOR₂₆; R₂₆, at each occurrence, is independently: (a) alkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) aryl, which may be optionallysubstituted with one or more R₄₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₄₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₄₀'s, 11)halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13) —COOH, 14) (C₂-C₆)-alkynyl,15) —COR₃₆, or 16) —COOR₃₆; or (b) hydrogen; R₃₆, at each occurrence, isindependently alkyl, aryl or heteroaryl, wherein the alkyl, aryl orheteroaryl may be optionally substituted with one or more R₄₀'s; and R₄₀is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl,haloalkyloxy, alkenyl, arylalkyloxy, alkynyl, cycloalkyl orcycloalkylalkyl.
 10. A compound of claim 1, wherein: A is:

B is:

C is:

R₁ is: (a) —C(O)NHR₃, wherein the R₃ is:

(b) —C(O)NR₂R₃, wherein the NR₂R₃ is:

(c) —C(O)OR₄ wherein the R₄ is:

(d) —SO₂R₅ wherein the R₅ is:

(e) —CSNHR₇ wherein the R₇ is:

(f) —CH₂R₈ wherein the R₈ is:

(g) —C(S)R₃ wherein the R₃ is:

(h) —C(═NR₃)Oalkyl wherein the R₃ is:


11. A compound of claim 2, wherein: A is:

B is:

C is:

R₁ is H or: (a) —C(O)NHR₃, wherein the R₃ is:

(b) —C(O)NR₂R₃, wherein the NR₂R₃ is:

(c) —C(O)OR₄ wherein the R₄ is:

(d) —SO₂R₅ wherein the R₅ is:

(e) —CSNHR₇ wherein the R₇ is:

(f) —CH₂R₈ wherein the R₈ is:

(g) —C(S)R₃, wherein R₃:


12. A compound of claim 1, wherein the compound is exemplified in theexamples.
 13. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 14. Thepharmaceutical composition of claim 13 further comprising at least oneadditional therapeutic agent.
 15. A method for treating, preventing orslowing the progression of Alzheimer's, atherosclerosis, venousthrombosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal by administering to amammal in need of such treatment an atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia treating, preventing or slowing amountof a compound of formula Ia or Ib

or stereoisomers or prodrugs or pharmaceutically acceptable salt formsthereof, wherein: A is phenyl, which is substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)═O, 17) —S(O)_(p)R₆, 18) —SO₂NHR₆, 19) —COOR₆, 20) —NHC(CN)NHR₆, 21)—CONR₆R₆, 22) (C₂-C₆)-alkynyl, which may be optionally substituted withone or more R₂₀'s, 23) (C₂-C₆)-alkenyl, which may be optionallysubstituted with one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆, 26)—OCONR₆R₆, or 27) cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or any two adjacent substituents may join together toform a 4- to 8-membered ring, which optionally may contain 1-4heteroatoms selected from N, O, and S and be optionally substituted withone or more R₂₀'s; B is: (a) phenyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) arylalkyl, which may be optionally substituted with one ormore R₂₀'s, 10) heteroaryl, which may be optionally substituted with oneor more R₂₀'s, 11) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 12) heterocyclyl, which may be optionallysubstituted with one or more R₂₀'s, 13) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)—COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20)—CONR₆R₆; and 21) cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or (b) heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17)—SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆; and 21)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;C is: (a) alkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆,15) —SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (b) alkenyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl; and 15) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; or (d) heterocyclo, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; R₁ is H, —C(O)R₃,—C(O)NR₂R₃, —C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₈, or —C(S)R₃; R₂ is:(a) H; (b) alkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)—COOR₆, 19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionallysubstituted with one or more R₂₀'s; (c) alkenyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20)—SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; or (d) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16)—COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, 20)(C₂-C₆)-alkynyl; and 21) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆,19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionallysubstituted with one or more R₂₀'s; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) —(C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (f) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆,20) —SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or R₂ and R₃ aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₄ is: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) (C₂-C₆)-alkenyl; or (e) (C₂-C₆)-alkynyl; R₅ is arylalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;R₆, at each occurrence, is independently: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, which maybe optionally substituted with one or more R₂₀'s; (c) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; (e) heterocyclyl, other than heteroaryl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₉R₁₀, 9) aryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₂₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₇ is aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; R₈ canindependently be: (a) H; (b) alkyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 10) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) —(C₂-C₆)-alkynyl, 17)—COR₂₆, 18) —S(O)_(p)R₂₆, 19) —SO₂NHR₂₆, 20) —COOR₂₆, 21) —NHC(CN)NHR₂₆;and 22) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (c) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (d) cycloalkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (e) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; or (f) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₈'s aretaken together to form a 3- to 9-membered ring, which may optionallycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₉ and R₁₀ are independently: (a)hydrogen; (b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R₂₀'s; (c)—[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may be optionallysubstituted with one or more R₂₀'s; (d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl optionally substituted with one or more R₂₀'s; (f)—CONR₂₆R₂₆; (g) —(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j)—SO₂NHR₂₆; (k) —COOR₂₆; (l) —NHC(CN)NHR₂₆; or m)—[(C═O)O_(r)]_(s)cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or R₉ and R₁₀ are taken together with the nitrogen towhich both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₂₀'s; R₂₀ is: (a) halo; (b)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) ═O; (q) —(C₂-C₆)-alkynyl; (r) —COR₂₆; (s)—S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u) —COOR₂₆; (v) —NHC(CN)NHR₂₆; (w)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(x) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (y) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s)cycloalkyl; (t) cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w)—SO₂NHR₂₆; (x) —COOR₂₆; or (y) —NHC(CN)NHR₂₆; R₂₆, at each occurrence,is independently: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with oneor more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆; and 23)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17)—CONR₃₆R₃₆, 18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆,22) —SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₄₀'s; (d) heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₄₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; or two R₂₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₄₀'s; R₂₉ and R₃₀ are independentlyhydrogen, —[(C═O)O_(r)]_(s)aryl, —[(C═O)O_(r)]_(s)alkenyl,—[(C═O)O_(r)]_(s)alkyl, heterocyclyl, alkynyl, —COR₃₆, —S(O)_(p)R₃₆,—SO₂NHR₃₆, —COOR₃₆, —C(CN)NHR₃₆, or cycloalkyl, wherein the aryl, alkyl,alkenyl, cycloalkyl or heterocyclyl may be optionally substituted withone or more R₄₀'s; or R₂₉ and R₃₀ are taken together with the nitrogento which both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₄₀'s; R₃₆, at each occurrence,is independently alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl,other than heteroaryl, wherein the alkyl, aryl, cycloalkyl, heteroarylor heterocyclyl may be optionally substituted with one or more R₄₀'s;R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉,—S(O)_(p)R₄₉, —SO₂NHR₄₉, —COOR₄₉, or —NHC(CN)NHR₄₉; R₄₉ and R₅₀, at eachoccurrence, are independently hydrogen, alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl; r is 0 to 5; s is 0to 4; and p is 1 or 2; excluding compounds having the following formula:


16. A method for treating, preventing or slowing the progression of adisease requiring cholesteryl ester transfer protein inhibitor therapywhich comprises administering, concurrently or sequentially, to a mammalin need of treatment, prevention or slowing a therapeutically effectiveamount of a compound of formula Ia or Ib

or stereoisomers or prodrugs or pharmaceutically acceptable salt formsthereof, and at least one additional therapeutic agent, wherein: A isphenyl, which is substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) ═O, 17)—S(O)_(p)R₆, 18) —SO₂NHR₆, 19) —COOR₆, 20) —NHC(CN)NHR₆, 21) —CONR₆R₆,22) (C₂-C₆)-alkynyl, which may be optionally substituted with one ormore R₂₀'s, 23) (C₂-C₆)-alkenyl, which may be optionally substitutedwith one or more R₂₀'s, 24) —OCOR₆, 25) —OCOOR₆, 26) —OCONR₆R₆, or 27)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or any two adjacent substituents may join together to form a 4- to8-membered ring, which optionally may contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R₂₀'s; Bis: (a) phenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆;and 21) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; or (b) heteroaryl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, 20) —CONR₆R₆;and 21) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; C is: (a) alkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆,15) —SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (b) alkenyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl; and 15) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; or (d) heterocyclo, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 10) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14) —S(O)_(p)R₆, 15)—SO₂NHR₆, 16) —COOR₆, 17) —NHC(CN)NHR₆; and 18) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; R₁ is H, —C(O)R₃,—C(O)NR₂R₃, —C(O)OR₄, —SO₂R₅, —C(S)NHR₇, —CR₈R₈R₈, or —C(S)R₃; R₂ is:(a) H; (b) alkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)heteroaryl, which may be optionally substituted with one or more R₂₀'s,10) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 11) halo(C₁-C₆)alkyl, 12) —COR₆, 13) —CONR₆R₆, 14)(C₂-C₆)-alkenyl, 15) (C₂-C₆)-alkynyl, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18)—COOR₆, 19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionallysubstituted with one or more R₂₀'s; (c) alkenyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆, 20)—SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; or (d) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CO(C₁-C₆)-alkyl, 16)—COOH, 17) —CO₂ (C₁-C₆)-alkyl, 18) —CONR₆R₆, 19) (C₂-C₆)-alkenyl, 20)(C₂-C₆)-alkynyl; and 21) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; R₃ is: (a) alkyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) heteroaryl, which may beoptionally substituted with one or more R₂₀'s, 10) heterocyclyl, whichmay be optionally substituted with one or more R₂₀'s, 11)halo(C₁-C₆)alkyl, 12) —CONR₆R₆, 13) (C₂-C₆)-alkenyl, 14)(C₂-C₆)-alkynyl, 15) —COR₆, 16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆,19) —NHC(CN)NHR₆; and 20) cycloalkyl, which may be optionallysubstituted with one or more R₂₀'s; (b) aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) —(C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (f) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) (C₂-C₆)-alkynyl, 18) —COR₆, 19) —S(O)_(p)R₆,20) —SO₂NHR₆, 21) —COOR₆, 22) —NHC(CN)NHR₆; and 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or R₂ and R₃ aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₄ is: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(c) cycloalkyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆,16) (C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) (C₂-C₆)-alkenyl; or (e) (C₂-C₆)-alkynyl; R₅ is arylalkyl, which maybe optionally substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) —CONR₆R₆, 16)(C₂-C₆)-alkenyl, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20)—S(O)_(p)R₆, 21) —SO₂NHR₆, 22) —COOR₆, 23) —NHC(CN)NHR₆; and 24)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;R₆, at each occurrence, is independently: (a) alkyl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heterocyclyl,which may be optionally substituted with one or more R₂₀'s, 12)halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15) —CONR₃₆R₃₆, 16)═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆, 20) —SO₂NHR₃₆,21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, which may beoptionally substituted with one or more R₂₀'s; (b) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17) —CONR₃₆R₃₆,18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆, 22)—SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, which maybe optionally substituted with one or more R₂₀'s; (c) cycloalkyl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(d) heteroaryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₂₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₂₀'s; (e) heterocyclyl, other than heteroaryl, whichmay be optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀, 9) aryl, which may beoptionally substituted with one or more R₂₀'s, 10) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₉R₁₀, 9) aryl, which may be optionally substituted with one or moreR₂₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₉R₁₀,9) aryl, which may be optionally substituted with one or more R₂₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₂₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₇ is aryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; R₈ canindependently be: (a) H; (b) alkyl, which may be optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7)—NR₉R₁₀, 8) aryl, which may be optionally substituted with one or moreR₂₀'s, 9) heteroaryl, which may be optionally substituted with one ormore R₂₀'s, 10) heterocyclyl, which may be optionally substituted withone or more R₂₀'s, 11) halo(C₁-C₆)alkyl, 12) (C₂-C₆)-alkenyl, 13)aryl(C₂-C₆)-alkynyl, 14) —CONR₂₆R₂₆, 15) ═O, 16) —(C₂-C₆)-alkynyl, 17)—COR₂₆, 18) —S(O)_(p)R₂₆, 19) —SO₂NHR₂₆, 20) —COOR₂₆, 21) —NHC(CN)NHR₂₆;and 22) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (c) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (d) cycloalkyl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; (e) heteroaryl, which may be optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀,8) aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15)(C₂-C₆)-alkenyl, 16) —CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19)—COR₂₆, 20) —S(O)_(p)R₂₆, 21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆;and 24) cycloalkyl, which may be optionally substituted with one or moreR₂₀'s; or (f) heterocyclyl, other than heteroaryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₂₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, 14) halo(C₁-C₆)alkyl, 15) (C₂-C₆)-alkenyl, 16)—CONR₂₆R₂₆, 17) ═O, 18) (C₂-C₆)-alkynyl, 19) —COR₂₆, 20) —S(O)_(p)R₂₆,21) —SO₂NHR₂₆, 22) —COOR₂₆, 23) —NHC(CN)NHR₂₆; and 24) cycloalkyl, whichmay be optionally substituted with one or more R₂₀'s; or two R₈'s aretaken together to form a 3- to 9-membered ring, which may optionallycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₂₀'s; R₉ and R₁₀ are independently: (a)hydrogen; (b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R₂₀'s; (c)—[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may be optionallysubstituted with one or more R₂₀'s; (d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R₂₀'s;(e) heterocyclyl optionally substituted with one or more R₂₀'s; (f)—CONR₂₆R₂₆; (g) —(C₂-C₆)-alkynyl; (h) —COR₂₆; (i) —S(O)_(p)R₂₆; (j)—SO₂NHR₂₆; (k) —COOR₂₆; (l) —NHC(CN)NHR₂₆; or m)—[(C═O)O_(r)]_(s)cycloalkyl, which may be optionally substituted withone or more R₂₀'s; or R₉ and R₁₀ are taken together with the nitrogen towhich both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₂₀'s; R₂₀ is: (a) halo; (b)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₁'s; (c) —OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g)—NR₂₉R₃₀; (h) aryl, which may be optionally substituted with one or moreR₂₁'s; (i) arylalkyl, which may be optionally substituted with one ormore R₂₁'s; (j) heteroaryl, which may be optionally substituted with oneor more R₂₁'s; (k) heteroarylalkyl, which may be optionally substitutedwith one or more R₂₁'s; (l) heterocyclyl, which may be optionallysubstituted with one or more R₂₁'s; (m) heterocyclylalkyl, which may beoptionally substituted with one or more R₂₁'s; (n) halo(C₁-C₆)alkyl; (o)(C₂-C₆)-alkenyl; (p) ═O; (q) —(C₂-C₆)-alkynyl; (r) —COR₂₆; (s)—S(O)_(p)R₂₆; (t) —SO₂NHR₂₆; (u) —COOR₂₆; (v) —NHC(CN)NHR₂₆; (w)cycloalkyl, which may be optionally substituted with one or more R₂₁'s;(x) cycloalkylalkyl, which may be optionally substituted with one ormore R₂₁'s; or (y) —CONR₂₆R₂₆; R₂₁ is: (a) halo; (b) (C₁-C₆)-alkyl; (c)—OR₂₆; (d) (C₁-C₆)-alkylthio; (e) cyano; (f) nitro; (g) —NR₂₉R₃₀; (h)aryl; (i) arylalkyl; (j) heteroaryl; (k) heteroarylalkyl; (l)heterocyclyl; (m) heterocyclylalkyl; (n) halo(C₁-C₆)alkyl; (o)—CONR₂₆R₂₆; (p) (C₂-C₆)-alkenyl; (q) ═O; (r) (C₂-C₆)-alkynyl; (s)cycloalkyl; (t) cycloalkylalkyl; (u) —COR₂₆; (v) —S(O)_(p)R₂₆; (w)—SO₂NHR₂₆; (x) —COOR₂₆; or (y) —NHC(CN)NHR₂₆; R₂₆, at each occurrence,is independently: (a) alkyl, which may be optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with oneor more R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆; and 23)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(b) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) —COOH, 17)—CONR₃₆R₃₆, 18) ═O, 19) (C₂-C₆)-alkynyl, 20) —COR₃₆, 21) —S(O)_(p)R₃₆,22) —SO₂NHR₃₆, 23) —COOR₃₆, 24) —NHC(CN)NHR₃₆; and 25) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; (c) cycloalkyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)arylalkyl, which may be optionally substituted with one or more R₄₀'s,11) heteroaryl, which may be optionally substituted with one or moreR₄₀'s, 12) heteroarylalkyl, which may be optionally substituted with oneor more R₄₀'s, 13) heterocyclyl, which may be optionally substitutedwith one or more R₄₀'s, 14) heterocyclylalkyl, which may be optionallysubstituted with one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16)(C₂-C₆)-alkenyl, 17) —COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl,21) —COR₃₆, 22) —S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25)—NHC(CN)NHR₃₆; and 26) cycloalkyl, which may be optionally substitutedwith one or more R₄₀'s; (d) heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(e) heterocyclyl, other than heteroaryl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, which may beoptionally substituted with one or more R₄₀'s, 4) —OR₃₆, 5)(C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀, 9) aryl, which maybe optionally substituted with one or more R₄₀'s, 10) arylalkyl, whichmay be optionally substituted with one or more R₄₀'s, 11) heteroaryl,which may be optionally substituted with one or more R₄₀'s, 12)heteroarylalkyl, which may be optionally substituted with one or moreR₄₀'s, 13) heterocyclyl, which may be optionally substituted with one ormore R₄₀'s, 14) heterocyclylalkyl, which may be optionally substitutedwith one or more R₄₀'s, 15) halo(C₁-C₆)alkyl, 16) (C₂-C₆)-alkenyl, 17)—COOH, 18) —CONR₃₆R₃₆, 19) ═O, 20) (C₂-C₆)-alkynyl, 21) —COR₃₆, 22)—S(O)_(p)R₃₆, 23) —SO₂NHR₃₆, 24) —COOR₃₆, 25) —NHC(CN)NHR₃₆; and 26)cycloalkyl, which may be optionally substituted with one or more R₄₀'s;(f) hydrogen; (g) alkynyl, which may be optionally substituted with oneor more substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, which may be optionally substituted with one ormore R₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8)—NR₂₉R₃₀, 9) aryl, which may be optionally substituted with one or moreR₄₀'s, 10) heteroaryl, which may be optionally substituted with one ormore R₄₀'s, 11) heterocyclyl, which may be optionally substituted withone or more R₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH,15) —CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19)—S(O)_(p)R₃₆, 20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23)cycloalkyl, which may be optionally substituted with one or more R₂₀'s;or (h) alkenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₄₀'s, 4) —OR₃₆, 5) (C₁-C₆)-alkylthio, 6) cyano, 7) nitro, 8) —NR₂₉R₃₀,9) aryl, which may be optionally substituted with one or more R₄₀'s, 10)heteroaryl, which may be optionally substituted with one or more R₄₀'s,11) heterocyclyl, which may be optionally substituted with one or moreR₄₀'s, 12) halo(C₁-C₆)alkyl, 13) (C₂-C₆)-alkenyl, 14) —COOH, 15)—CONR₃₆R₃₆, 16) ═O, 17) (C₂-C₆)-alkynyl, 18) —COR₃₆, 19) —S(O)_(p)R₃₆,20) —SO₂NHR₃₆, 21) —COOR₃₆, 22) —NHC(CN)NHR₃₆, or 23) cycloalkyl, whichmay be optionally substituted with one or more R₄₀'s; or two R₂₆'s aretaken together to form a 3- to 9-membered ring, which optionally maycontain 1-4 heteroatoms selected from N, O, and S and be optionallysubstituted with one or more R₄₀'s; R₂₉ and R₃₀ are independentlyhydrogen, —[(C═O)O_(r)]_(s)aryl, —[(C═O)O_(r)]_(s)alkenyl,—[(C═O)O_(r)]_(s)alkyl, heterocyclyl, alkynyl, —COR₃₆, —S(O)_(p)R₃₆,—SO₂NHR₃₆, —COOR₃₆, —C(CN)NHR₃₆, or cycloalkyl, wherein the aryl, alkyl,alkenyl, cycloalkyl or heterocyclyl may be optionally substituted withone or more R₄₀'s; or R₂₉ and R₃₀ are taken together with the nitrogento which both are attached to form a 3- to 8-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with one or more R₄₀'s; R₃₆, at each occurrence,is independently alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl,other than heteroaryl, wherein the alkyl, aryl, cycloalkyl, heteroarylor heterocyclyl may be optionally substituted with one or more R₄₀'s;R₄₀ is halo, —OH, alkyl, alkyloxy, alkylthio, cyano, nitro, —NR₄₉R₅₀,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, haloalkyl, haloalkyloxy, —CONR₄₉R₅₀, alkenyl,arylalkyloxy, ═O, alkynyl, cycloalkyl, cycloalkylalkyl, —COR₄₉,—S(O)_(p)R₄₉, —SO₂NHR₄₉, —COOR₄₉, or —NHC(CN)NHR₄₉; R₄₉ and R₅₀, at eachoccurrence, are independently hydrogen, alkyl, aryl, cycloalkyl,heteroaryl or heterocyclyl, other than heteroaryl; r is 0 to 5; s is 0to 4; and p is 1 or 2; excluding compounds having the following formula:


17. A process for the preparation of mainly a compound of formula WW,B—OCF₂CF₂H, comprising reducing a mixture comprised of a compound offormula WW and a compound of formula YY, B—OCF₂CF₂Br, with zinc dustunder acidic conditions, wherein B is phenyl, which may be optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) (C₁-C₆)-alkyl, which may be optionallysubstituted with one or more R₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5)cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may be optionallysubstituted with one or more R₂₀'s, 9) arylalkyl, which may beoptionally substituted with one or more R₂₀'s, 10) heteroaryl, which maybe optionally substituted with one or more R₂₀'s, 11) heteroarylalkyl,which may be optionally substituted with one or more R₂₀'s, 12)heterocyclyl, which may be optionally substituted with one or moreR₂₀'s, 13) heterocyclylalkyl, which may be optionally substituted withone or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16) —S(O)_(p)R₆,17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20) —CONR₆R₆ and R₆, R₉,R₁₀ and R₂₀ are as defined in claim
 1. 18. A process for the preparationof a mixture comprised of a compound of formula WW and a compound offormula YY, B—OCF₂CF₂Br, comprising reacting a compound of formula ZZ,B—OH, with 1,2-dibromotetrafluoroethane under basic conditions, whereinB is phenyl, which may be optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2)(C₁-C₆)-alkyl, which may be optionally substituted with one or moreR₂₀'s, 3) —OR₆, 4) (C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8)aryl, which may be optionally substituted with one or more R₂₀'s, 9)arylalkyl, which may be optionally substituted with one or more R₂₀'s,10) heteroaryl, which may be optionally substituted with one or moreR₂₀'s, 11) heteroarylalkyl, which may be optionally substituted with oneor more R₂₀'s, 12) heterocyclyl, which may be optionally substitutedwith one or more R₂₀'s, 13) heterocyclylalkyl, which may be optionallysubstituted with one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆,16) —S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆ and R₆, R₉, R₁₀ and R₂₀ are as defined in claim
 1. 19. Aprocess for the preparation of a compound of formula ZZ comprisingreacting a compound of formula AAA, B—F, with potassiumtrimethylsilanoate in a solvent other than THF, wherein B is phenyl,which may be optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) (C₁-C₆)-alkyl, whichmay be optionally substituted with one or more R₂₀'s, 3) —OR₆, 4)(C₁-C₆)-alkylthio, 5) cyano, 6) nitro, 7) —NR₉R₁₀, 8) aryl, which may beoptionally substituted with one or more R₂₀'s, 9) arylalkyl, which maybe optionally substituted with one or more R₂₀'s, 10) heteroaryl, whichmay be optionally substituted with one or more R₂₀'s, 11)heteroarylalkyl, which may be optionally substituted with one or moreR₂₀'s, 12) heterocyclyl, which may be optionally substituted with one ormore R₂₀'s, 13) heterocyclylalkyl, which may be optionally substitutedwith one or more R₂₀'s, and 14) halo(C₁-C₆)alkyl, 15) —COR₆, 16)—S(O)_(p)R₆, 17) —SO₂NHR₆, 18) —COOR₆, 19) —NHC(CN)NHR₆, and 20)—CONR₆R₆ and R₆, R₉, R₁₀ and R₂₀ are as defined in claim 1.